Methods of increasing tonic inhibition and treating secondary insomnia

ABSTRACT

Methods of increasing tonic inhibition in a subject in need thereof, for example a subject with Fragile X syndrome or Angelman syndrome are disclosed. Methods of treating secondary insomnia in a subject with a neurodegenerative disease or disorder are also disclosed. The methods can include administering the subject an effective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivative thereof, or a pharmaceutically acceptable salt thereof, increase tonic inhibition in neurons of the subject; to increase slow wave sleep (SWS) and/or slow wave activity (SWA), normalize sleep architecture, reduce secondary insomnia, increase non-rapid eye movement (NREM) sleep, increase sleep continuity, enhance delta activity within NREM, increase or improve total sleep time (TST), increase or improve sleep efficiency, reduce total time awake (TAA), reduce number of awakenings (NWA), reduce latency to persistent sleep (LPS), or to reduce wake after sleep onset (WASO), in the subject, or any combination thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of and priority to U.S. ProvisionalApplication No. 62/526,553, filed Jun. 29, 2017, and to U.S. ProvisionalApplication No. 62/008,939, filed Jun. 6, 2014, and is a continuation ofU.S. patent application Ser. No. 16/023,282, filed Jun. 29, 2018, whichis a continuation of U.S. patent application Ser. No. 15/618,736, filedJun. 9, 2017, which is a continuation U.S. patent application Ser. No.15/343,690, filed Nov. 4, 2016, now U.S. Pat. No. 9,744,159, issued onAug. 29, 2017, which is a continuation of U.S. patent application Ser.No. 14/729,910, filed Jun. 3, 2015, all of which are incorporated hereinby reference in their respective entireties.

FIELD OF THE INVENTION

The field of the invention generally relates to methods of using acomposition including 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol(THIP), a derivative thereof, or a pharmaceutically acceptable saltthereof for treating diseases and disorders characterized by secondaryinsomnia and/or defects or deficiencies in tonic inhibition.

BACKGROUND OF THE INVENTION

Although many advances have been made, the treatments forneurodegenerative diseases and neurogenetic diseases remain largelyinadequate.

In some cases, neurological diseases are linked by an underlyingpathophysiology, for example, Fragile X syndrome and Angelman syndromeare linked by loss of tonic inhibition in certain tissues of the brain.In some cases, neurological diseases are linked by symptoms. Forexample, although different neurodegenerative diseases are characterizedby a broad range of symptoms, many of the diseases and disorders arelinked by one or more sleep-related disorders, such as insomnia,disrupted sleep, and altered sleep architecture (Jennum, et al.,“CHAPTER 39: Sleep disorders in neurodegenerative disorders and stroke”,European Handbook of Neurological Management, Volume 1, 2nd Edition (Ed.Gilhus, et al.) Blackwell Publishing Ltd. 2011)).

For diseases such as Huntington's disease, Parkinson's disease,Amyotrophic Lateral Sclerosis, Alzheimer's disease, Fragile X syndrome,and Angelman syndrome, treatments are very limited and cures do notexist. Therefore, there is a need for additional therapeutic options fortreating neurodegenerative diseases, neurogenetic, and other centralnervous system disorders.

Accordingly, it is an object of the invention to provide methods fortreating and preventing secondary insomnia in subjects with neurologicaldiseases.

It is another object of the invention to provide methods for increasingtonic inhibition in a subject in need thereof.

SUMMARY OF THE INVENTION

Methods of increasing tonic inhibition of neurons in a subject,particularly subjects with Fragile X syndrome or Angelman syndrome areprovided. Methods of treating secondary insomnia in a subject with aneurodegenerative disease or a central nervous system disorder are alsoprovided. The methods typically include administering to the subject apharmaceutical composition including an effective amount of4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivativethereof and a pharmaceutically acceptable carrier or excipient toincrease tonic inhibition of neurons in the subject, to increase slowwave sleep (SWS) and/or slow wave activity (SWA), normalize sleeparchitecture, reduce secondary insomnia, increase non-rapid eye movement(NREM) sleep, increase sleep continuity, enhance delta activity withinNREM, increase or improve total sleep time (TST), increase or improvesleep efficiency, reduce total time awake (TAA), reduce number ofawakenings (NWA), reduce latency to persistent sleep (LPS), or reducewake after sleep onset (WASO) in the subject, or any combination thereofin the subject.

In particular embodiments, the subjects suffering from secondaryinsomnia have Parkinson's Disease (PD) or a PD-related disorder,Alzheimer's Disease (AD), Huntington's disease, Parkinson's disease,Amyotrophic lateral sclerosis, or Alzheimer's disease.

In the most preferred embodiments, the THIP or derivative thereof isTHIP or a pharmaceutically acceptable salt thereof. The THIP orderivative thereof can be the singular active agent or one of two ormore active agents in the pharmaceutical composition. The pharmaceuticalcomposition is formulated for extended release. The pharmaceuticalcomposition can be administered transdermally, for example, bycontacting a transdermal patch including the pharmaceutical compositionwith the skin of the subject. In a particular embodiment, the dailydosage of the THIP or derivative thereof is between about 2.5 mg and 50mg per day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar graph depicting average body weight of mice used in theResident Intruder Test prescreen of Example 1.

FIG. 2 is a bar graph depicting attack latency results of the ResidentIntruder Test prescreen of Example 1.

FIG. 3 is a bar graph depicting attack frequency results of the ResidentIntruder Test prescreen of Example 1.

FIG. 4 is a bar graph depicting average body weight of mice used in theResident Intruder Test of Example 1.

FIG. 5 is a bar graph depicting attack latency results of the ResidentIntruder Test 1 of Example 1.

FIG. 6 is a bar graph depicting attack frequency results of the ResidentIntruder Test 1 of Example 1.

FIG. 7 is a graph depicting the effect of gaboxadol on locomotoractivity on male C57 mice.

FIG. 8 is a graph depicting the effect of gaboxadol on locomotoractivity on male Balb/Cbyj mice.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

As used herein, the term “carrier” or “excipient” refers to an organicor inorganic ingredient, natural or synthetic inactive ingredient in aformulation, with which one or more active ingredients are combined.

As used herein, the term “pharmaceutically acceptable” means a non-toxicmaterial that does not interfere with the effectiveness of thebiological activity of the active ingredients.

As used herein, the terms “effective amount” or “therapeuticallyeffective amount” means a dosage sufficient to alleviate one or moresymptoms of a disorder, disease, or condition being treated, or tootherwise provide a desired pharmacologic and/or physiologic effect. Theprecise dosage will vary according to a variety of factors such assubject-dependent variables (e.g., age, immune system health, etc.), thedisease or disorder being treated, as well as the route ofadministration and the pharmacokinetics of the agent being administered.

As used herein, the term “prevention” or “preventing” means toadminister a composition to a subject or a system at risk for or havinga predisposition for one or more symptom caused by a disease or disorderto cause cessation of a particular symptom of the disease or disorder, areduction or prevention of one or more symptoms of the disease ordisorder, a reduction in the severity of the disease or disorder, thecomplete ablation of the disease or disorder, stabilization or delay ofthe development or progression of the disease or disorder.

II. Compositions Including Gaboxadol or a Derivative Thereof

Methods of using 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP),a derivative thereof, or a pharmaceutically acceptable salt thereof fortreating secondary insomnia, disturbed sleep architecture, or acombination thereof in a subject are disclosed. In some embodiments, thesubject has or is at risk of developing a neurodegenerative disease or acentral nervous system disorder. In the most preferred embodiments, thesubject suffers from secondary insomnia and/or disturbed sleeparchitecture due to a neurodegenerative disease or a central nervoussystem disorder. As discussed in more detail below, the methodstypically include administering to a subject in need thereof aneffective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol(THIP), a derivative thereof, or a pharmaceutically acceptable saltthereof to increase slow wave sleep, normalize sleep architecture, or acombination thereof a subject. In some embodiments, clinical symptoms ofa neurodegenerative disease or central nervous system disorder arereduced.

Methods of using 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP),a derivative thereof, or a pharmaceutically acceptable salt thereof forincreasing tonic inhibition are also provided. The methods can be usedto increase tonic inhibition in a subject with a disease or disordercharacterized a defect or deficiency in tonic inhibition, for exampleFragile X Syndrome or Angelman Syndrome.

A. 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP)

The compositions for use in the disclosed methods of treating secondaryinsomnia include 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (alsoreferred to as THIP and gaboxadol), a derivative thereof, orpharmaceutically acceptable salt thereof, or a structurally relatedcompound. THIP, as well as derivatives and structurally relatedcompounds, and methods of making thereof are known in the art. See, forexample, U.S. Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO2005/094820 each of which is specifically incorporated by referenceherein in its entirety. Particularly preferred compounds are discussedin more detail below.

In some embodiments, the compound is of the formula Ia

-   -   4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a        tautomer, isomer, epimer, or diastereoisomer thereof.

THIP is well tolerated and is a very potent GABA agonist having a veryspecific activity, and being inactive as a GABA-uptake inhibitor.Gaboxadol is a selective extrasynaptic GABA_(A) agonist (SEGA) (Deacon,et al., Sleep, 30(3):281-287 (2007)). The GABA_(A) receptor is apentameric transmembrane protein that has 5 subunits forming a centralanion channel. Gaboxadol binds at the interface between the α and βsubunits, the same site to which the endogenous GABA ligand binds.Gaboxadol exerts direct effects on chloride conductance, independent ofGABA and it can directly activate extrasynaptically located δ-containingreceptors via interaction with the GABA binding site. Extrasynapticδ-containing receptors are predominantly expressed in the thalamus,cerebral cortex, and limbic system. These regions of the brain have beenimplicated in sleep regulation and synchronization of cortical activity.

It is believed that the selective activity of the compound Ia isascribable to the particular position of the nitrogen atom in the6-membered ring in relation to the acidic hydroxy group in the5-membered ring.

Therefore, compound Ia and derivatives thereof, particularly derivativeswhich upon administration will be decomposed in situ to yield the parentcompound Ia, in particular compounds of the general formula I

wherein R″ is hydrogen, acetyl or a group of the general formula II

wherein R₅ is C₁₋₈ alkyl; phenyl; phenyl substituted in the 4-positionwith halogen, lower alkoxy, or lower alkyl; or phenylalkyl such asbenzyl or phenylethyl in which the phenyl group may be substituted inthe 4-position with halogen, lower alkoxy, or lower alkyl; and saltsthereof.

It is believed that the groups R″ which are different from hydrogen mayenhance the penetration of the compounds into the brain in that they mayenhance the ability of the compounds to pass the blood brain barrier,and will thereafter be split off in situ to yield the parent compound.Also, a prolonged effect of Ia may be obtained via decomposition in situof compounds wherein R″ is different from hydrogen, to yield the parentcompound.

“Lower alkyl”, “lower alkoxy”, and “lower alkyloxy” designate suchgroups containing 1-6 carbon atoms, preferably 1-4 atoms inclusive.

The compounds of the general formula I may exist in a tautomeric form,as shown by the formula I′

Formula I is to be understood as covering also this tautomeric form (I′)and mixtures of the two tautomeric forms.

Examples of compounds of the general formula I in which R″ is differentfrom hydrogen, are:6-acetyl-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol, methyl3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,ethyl3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,tert.butyl3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,phenyl3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,4-chlorophenyl3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,4-methoxyphenyl3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,benzyl3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate, andsalts thereof with bases.

Derivatives of THIP are known in the art. See, for examples, U.S. Pat.No. 4,353,910.

Preferred derivatives have the formula

wherein R is an alkyl group, branched or unbranched, having from one toseventeen carbon atoms inclusive, a phenyl group optionally substitutedwith one or two groups selected from lower alkyl, lower alkyloxy andhalogen, a phenylalkyl group, lower alkyloxy group or a —NHR₁ group,wherein R₁ is hydrogen, lower alkyl, phenyl or cyclohexyl, as well aspharmaceutically acceptable acid addition salts thereof.

Formula III as well as their pharmaceutically acceptable acid additionsalts show GABA-related activity at the same level as does the compoundTHIP, and some of the compounds also show a prolonged effect comparedwith THIP. They moreover show pronounced analgesic and myotonolyticeffects.

As examples of pharmaceutically acceptable salts of the compounds of thedisclosed formulae may be mentioned salts with inorganic acids.

Examples of salts of the compounds of the formulae are acid additionsalts thereof, such as pharmaceutically acceptable salts with inorganicacids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoricacids and the like, or with organic acids, such as organic carboxylicacids, e.g. acetic, propionic, glycolic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, glucuronic, benzoic, pamoic acid andthe like, or organic sulfonic acids, e.g. methane sulfonic, ethanesulfonic, benzene sulfonic, toluene sulfonic acid and the like, whichsalts may be prepared by procedures known per se, e.g. by adding theacid in question to the base, preferably in a solvent. Compounds of theformulae can form pharmaceutically acceptable salts with bases, such asmetal salts, e.g. sodium, potassium, calcium or aluminium salts, andammonium and substituted ammonium salts, e.g. salts of amines such astriethylamine, triethanolamine, ethylpiperidine, procaine, anddibenzylamine.

Throughout the description “THIP or a derivative thereof” is intended toinclude any form of the compound, such as the base (zwitter ion),pharmaceutically acceptable salts, e.g., pharmaceutically acceptableacid addition salts, hydrates or solvates of the base or salt, as wellas anhydrates, and also amorphous, or crystalline forms.

B. Formulations

The disclosed compounds can be formulated in a pharmaceuticalcomposition. Pharmaceutical compositions can be for administration byparenteral (intramuscular, intraperitoneal, intravenous (IV) orsubcutaneous injection), enteral, transdermal (either passively or usingiontophoresis or electroporation), or transmucosal (nasal, pulmonary,vaginal, rectal, or sublingual) routes of administration or usingbioerodible inserts and can be formulated in dosage forms appropriatefor each route of administration.

The compositions can be administered systemically.

Drugs can be formulated for immediate release, extended release, ormodified release. A delayed release dosage form is one that releases adrug (or drugs) at a time other than promptly after administration. Anextended release dosage form is one that allows at least a twofoldreduction in dosing frequency as compared to that drug presented as aconventional dosage form (e.g. as a solution or prompt drug-releasing,conventional solid dosage form). A modified release dosage form is onefor which the drug release characteristics of time course and/orlocation are chosen to accomplish therapeutic or convenience objectivesnot offered by conventional dosage forms such as solutions, ointments,or promptly dissolving dosage forms. Delayed release and extendedrelease dosage forms and their combinations are types of modifiedrelease dosage forms.

Formulations are prepared using a pharmaceutically acceptable “carrier”composed of materials that are considered safe and effective and may beadministered to an individual without causing undesirable biologicalside effects or unwanted interactions. The “carrier” is all componentspresent in the pharmaceutical formulation other than the activeingredient or ingredients. The term “carrier” includes, but is notlimited to, diluents, binders, lubricants, desintegrators, fillers, andcoating compositions.

“Carrier” also includes all components of the coating composition whichmay include plasticizers, pigments, colorants, stabilizing agents, andglidants. The delayed release dosage formulations may be prepared asdescribed in references such as “Pharmaceutical dosage form tablets”,eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989),“Remington—The science and practice of pharmacy”, 20th ed., LippincottWilliams & Wilkins, Baltimore, Md., 2000, and “Pharmaceutical dosageforms and drug delivery systems”, 6^(th) Edition, Ansel et. al., (Media,Pa.: Williams and Wilkins, 1995) which provides information on carriers,materials, equipment and process for preparing tablets and capsules anddelayed release dosage forms of tablets, capsules, and granules.

The compound can be administered to a subject with or without the aid ofa delivery vehicle. Appropriate delivery vehicles for the compounds areknown in the art and can be selected to suit the particular activeagent. For example, in some embodiments, the active agent(s) isincorporated into or encapsulated by, or bound to, a nanoparticle,microparticle, micelle, synthetic lipoprotein particle, or carbonnanotube. For example, the compositions can be incorporated into avehicle such as polymeric microparticles which provide controlledrelease of the active agent(s). In some embodiments, release of thedrug(s) is controlled by diffusion of the active agent(s) out of themicroparticles and/or degradation of the polymeric particles byhydrolysis and/or enzymatic degradation.

Suitable polymers include ethylcellulose and other natural or syntheticcellulose derivatives. Polymers which are slowly soluble and form a gelin an aqueous environment, such as hydroxypropyl methylcellulose orpolyethylene oxide, may also be suitable as materials for drugcontaining microparticles or particles. Other polymers include, but arenot limited to, polyanhydrides, poly (ester anhydrides), polyhydroxyacids, such as polylactide (PLA), polyglycolide (PGA),poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybut rate (PHB) andcopolymers thereof, poly-4-hydroxybutyrate (P4HB) and copolymersthereof, polycaprolactone and copolymers thereof, and combinationsthereof. In some embodiments, both agents are incorporated into the sameparticles and are formulated for release at different times and/or overdifferent time periods. For example, in some embodiments, one of theagents is released entirely from the particles before release of thesecond agent begins. In other embodiments, release of the first agentbegins followed by release of the second agent before the all of thefirst agent is released. In still other embodiments, both agents arereleased at the same time over the same period of time or over differentperiods of time.

1. Formulations for Parenteral Administration

Compounds and pharmaceutical compositions thereof can be administered inan aqueous solution, by parenteral injection. The formulation may alsobe in the form of a suspension or emulsion. In general, pharmaceuticalcompositions are provided including effective amounts of the activeagent(s) and optionally include pharmaceutically acceptable diluents,preservatives, solubilizers, emulsifiers, adjuvants and/or carriers.Such compositions include diluents sterile water, buffered saline ofvarious buffer content (e.g., Tris-HCl, acetate, phosphate), pH andionic strength; and optionally, additives such as detergents andsolubilizing agents (e.g., TWEEN® 20, TWEEN® 80 also referred to asPOLYSORBATE® 20 or 80), anti-oxidants (e.g., ascorbic acid, sodiummetabisulfite), and preservatives (e.g., Thimersol, benzyl alcohol) andbulking substances (e.g., lactose, mannitol). Examples of non-aqueoussolvents or vehicles are propylene glycol, polyethylene glycol,vegetable oils, such as olive oil and corn oil, gelatin, and injectableorganic esters such as ethyl oleate. The formulations may be lyophilizedand redissolved/resuspended immediately before use. The formulation maybe sterilized by, for example, filtration through a bacteria retainingfilter, by incorporating sterilizing agents into the compositions, byirradiating the compositions, or by heating the compositions.

2. Oral Immediate Release Formulations

Suitable oral dosage forms include tablets, capsules, solutions,suspensions, syrups, and lozenges. Tablets can be made using compressionor molding techniques well known in the art. Gelatin or non-gelatincapsules can prepared as hard or soft capsule shells, which canencapsulate liquid, solid, and semi-solid fill materials, usingtechniques well known in the art.

Examples of suitable coating materials include, but are not limited to,cellulose polymers such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate and hydroxypropyl methylcellulose acetate succinate; polyvinylacetate phthalate, acrylic acid polymers and copolymers, and methacrylicresins that are commercially available under the trade name Eudragit®(Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carrierssuch as plasticizers, pigments, colorants, glidants, stabilizationagents, pore formers and surfactants.

Optional pharmaceutically acceptable excipients present in thedrug-containing tablets, beads, granules or particles include, but arenot limited to, diluents, binders, lubricants, disintegrants, colorants,stabilizers, and surfactants. Diluents, also termed “fillers,” aretypically necessary to increase the bulk of a solid dosage form so thata practical size is provided for compression of tablets or formation ofbeads and granules. Suitable diluents include, but are not limited to,dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose,mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin,sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch,silicone dioxide, titanium oxide, magnesium aluminum silicate and powdersugar.

Binders are used to impart cohesive qualities to a solid dosageformulation, and thus ensure that a tablet or bead or granule remainsintact after the formation of the dosage forms. Suitable bindermaterials include, but are not limited to, starch, pregelatinizedstarch, gelatin, sugars (including sucrose, glucose, dextrose, lactoseand sorbitol), polyethylene glycol, waxes, natural and synthetic gumssuch as acacia, tragacanth, sodium alginate, cellulose, includinghydorxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose,and veegum, and synthetic polymers such as acrylic acid and methacrylicacid copolymers, methacrylic acid copolymers, methyl methacrylatecopolymers, aminoalkyl methacrylate copolymers, polyacrylicacid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples ofsuitable lubricants include, but are not limited to, magnesium stearate,calcium stearate, stearic acid, glycerol behenate, polyethylene glycol,talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or“breakup” after administration, and generally include, but are notlimited to, starch, sodium starch glycolate, sodium carboxymethylstarch, sodium carboxymethylcellulose, hydroxypropyl cellulose,pregelatinized starch, clays, cellulose, alginine, gums or cross linkedpolymers, such as cross-linked PVP (Polyplasdone XL from GAF ChemicalCorp).

Stabilizers are used to inhibit or retard drug decomposition reactionswhich include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surfaceactive agents. Suitable anionic surfactants include, but are not limitedto, those containing carboxylate, sulfonate and sulfate ions. Examplesof anionic surfactants include sodium, potassium, ammonium of long chainalkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodiumbis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodiumlauryl sulfate. Cationic surfactants include, but are not limited to,quaternary ammonium compounds such as benzalkonium chloride,benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzylammonium chloride, polyoxyethylene and coconut amine. Examples ofnonionic surfactants include ethylene glycol monostearate, propyleneglycol myristate, glyceryl monostearate, glyceryl stearate,polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates,polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylenetridecyl ether, polypropylene glycol butyl ether, POLOXAMER® 401,stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallowamide. Examples of amphoteric surfactants include sodiumN-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

If desired, the tablets, beads granules or particles may also containminor amount of nontoxic auxiliary substances such as wetting oremulsifying agents, dyes, pH buffering agents, and preservatives.

3. Extended Release Dosage Forms

The extended release formulations are generally prepared as diffusion orosmotic systems, for example, as described in “Remington—The science andpractice of pharmacy” (20th ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000). A diffusion system typically consists of twotypes of devices, reservoir and matrix, and is well known and describedin the art. The matrix devices are generally prepared by compressing thedrug with a slowly dissolving polymer carrier into a tablet form. Thethree major types of materials used in the preparation of matrix devicesare insoluble plastics, hydrophilic polymers, and fatty compounds.Plastic matrices include, but not limited to, methyl acrylate-methylmethacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymersinclude, but are not limited to, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and carbopol 934, polyethylene oxides. Fattycompounds include, but are not limited to, various waxes such ascarnauba wax and glyceryl tristearate.

Alternatively, extended release formulations can be prepared usingosmotic systems or by applying a semi-permeable coating to the dosageform. In the latter case, the desired drug release profile can beachieved by combining low permeable and high permeable coating materialsin suitable proportion.

The devices with different drug release mechanisms described above couldbe combined in a final dosage form comprising single or multiple units.Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, granules, etc.

An immediate release portion can be added to the extended release systemby means of either applying an immediate release layer on top of theextended release core using coating or compression process or in amultiple unit system such as a capsule containing extended and immediaterelease beads.

Extended release tablets containing hydrophilic polymers are prepared bytechniques commonly known in the art such as direct compression, wetgranulation, or dry granulation processes. Their formulations usuallyincorporate polymers, diluents, binders, and lubricants as well as theactive pharmaceutical ingredient. The usual diluents include inertpowdered substances such as any of many different kinds of starch,powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders. Typical diluents include, for example,various types of starch, lactose, mannitol, kaolin, calcium phosphate orsulfate, inorganic salts such as sodium chloride and powdered sugar.Powdered cellulose derivatives are also useful. Typical tablet bindersinclude substances such as starch, gelatin and sugars such as lactose,fructose, and glucose. Natural and synthetic gums, including acacia,alginates, methylcellulose, and polyvinylpyrrolidine can also be used.Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes canalso serve as binders. A lubricant is necessary in a tablet formulationto prevent the tablet and punches from sticking in the die. Thelubricant is chosen from such slippery solids as talc, magnesium andcalcium stearate, stearic acid and hydrogenated vegetable oils.

Extended release tablets containing wax materials are generally preparedusing methods known in the art such as a direct blend method, acongealing method, and an aqueous dispersion method. In a congealingmethod, the drug is mixed with a wax material and either spray-congealedor congealed and screened and processed.

4. Delayed Release Dosage Forms

Delayed release formulations are created by coating a solid dosage formwith a film of a polymer which is insoluble in the acid environment ofthe stomach, and soluble in the neutral environment of small intestines.

The delayed release dosage units can be prepared, for example, bycoating a drug or a drug-containing composition with a selected coatingmaterial. The drug-containing composition may be, e.g., a tablet forincorporation into a capsule, a tablet for use as an inner core in a“coated core” dosage form, or a plurality of drug-containing beads,particles or granules, for incorporation into either a tablet orcapsule. Preferred coating materials include bioerodible, graduallyhydrolyzable, gradually water-soluble, and/or enzymatically degradablepolymers, and may be conventional “enteric” polymers. Enteric polymers,as will be appreciated by those skilled in the art, become soluble inthe higher pH environment of the lower gastrointestinal tract or slowlyerode as the dosage form passes through the gastrointestinal tract,while enzymatically degradable polymers are degraded by bacterialenzymes present in the lower gastrointestinal tract, particularly in thecolon. Suitable coating materials for effecting delayed release include,but are not limited to, cellulosic polymers such as hydroxypropylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose,hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropylmethyl cellulose phthalate, methylcellulose,ethyl cellulose, cellulose acetate, cellulose acetate phthalate,cellulose acetate trimellitate and carboxymethylcellulose sodium;acrylic acid polymers and copolymers, preferably formed from acrylicacid, methacrylic acid, methyl acrylate, ethyl acrylate, methylmethacrylate and/or ethyl methacrylate, and other methacrylic resinsthat are commercially available under the tradename EUDRAGIT®. (RohmPharma; Westerstadt, Germany), including EUDRAGIT®. L30D-55 and L100-55(soluble at pH 5.5 and above), EUDRAGIT®. L-100 (soluble at pH 6.0 andabove), EUDRAGIT®. S (soluble at pH 7.0 and above, as a result of ahigher degree of esterification), and EUDRAGITS®. NE, RL and RS(water-insoluble polymers having different degrees of permeability andexpandability); vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetatecrotonic acid copolymer, and ethylene-vinyl acetate copolymer;enzymatically degradable polymers such as azo polymers, pectin,chitosan, amylose and guar gum; zein and shellac. Combinations ofdifferent coating materials may also be used. Multi-layer coatings usingdifferent polymers may also be applied.

The preferred coating weights for particular coating materials may bereadily determined by those skilled in the art by evaluating individualrelease profiles for tablets, beads and granules prepared with differentquantities of various coating materials. It is the combination ofmaterials, method and form of application that produce the desiredrelease characteristics, which one can determine only from the clinicalstudies.

The coating composition may include conventional additives, such asplasticizers, pigments, colorants, stabilizing agents, glidants, etc. Aplasticizer is normally present to reduce the fragility of the coating,and will generally represent about 10 wt. % to 50 wt. % relative to thedry weight of the polymer. Examples of typical plasticizers includepolyethylene glycol, propylene glycol, triacetin, dimethyl phthalate,diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethylcitrate, tributyl citrate, triethyl acetyl citrate, castor oil andacetylated monoglycerides. A stabilizing agent is preferably used tostabilize particles in the dispersion. Typical stabilizing agents arenonionic emulsifiers such as sorbitan esters, polysorbates andpolyvinylpyrrolidone. Glidants are recommended to reduce stickingeffects during film formation and drying, and will generally representapproximately 25 wt. % to 100 wt. % of the polymer weight in the coatingsolution. One effective glidant is talc. Other glidants such asmagnesium stearate and glycerol monostearates may also be used. Pigmentssuch as titanium dioxide may also be used. Small quantities of ananti-foaming agent, such as a silicone (e.g., simethicone), may also beadded to the coating composition.

Methods of Manufacturing

As will be appreciated by those skilled in the art and as described inthe pertinent texts and literature, a number of methods are availablefor preparing drug-containing tablets, beads, granules or particles thatprovide a variety of drug release profiles. Such methods include, butare not limited to, the following: coating a drug or drug-containingcomposition with an appropriate coating material, typically although notnecessarily incorporating a polymeric material, increasing drug particlesize, placing the drug within a matrix, and forming complexes of thedrug with a suitable complexing agent.

The delayed release dosage units may be coated with the delayed releasepolymer coating using conventional techniques, e.g., using aconventional coating pan, an airless spray technique, fluidized bedcoating equipment (with or without a Wurster insert). For detailedinformation concerning materials, equipment and processes for preparingtablets and delayed release dosage forms, see Pharmaceutical DosageForms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc.,1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems, 6.sup.th Ed. (Media, Pa.: Williams & Wilkins, 1995).

A preferred method for preparing extended release tablets is bycompressing a drug-containing blend, e.g., blend of granules, preparedusing a direct blend, wet-granulation, or dry-granulation process.Extended release tablets may also be molded rather than compressed,starting with a moist material containing a suitable water-solublelubricant. However, tablets are preferably manufactured usingcompression rather than molding. A preferred method for forming extendedrelease drug-containing blend is to mix drug particles directly with oneor more excipients such as diluents (or fillers), binders,disintegrants, lubricants, glidants, and colorants. As an alternative todirect blending, a drug-containing blend may be prepared by usingwet-granulation or dry-granulation processes. Beads containing theactive agent may also be prepared by any one of a number of conventionaltechniques, typically starting from a fluid dispersion. For example, atypical method for preparing drug-containing beads involves dispersingor dissolving the active agent in a coating suspension or solutioncontaining pharmaceutical excipients such as polyvinylpyrrolidone,methylcellulose, talc, metallic stearates, silicone dioxide,plasticizers or the like. The admixture is used to coat a bead core suchas a sugar sphere (or so-called “non-pareil”) having a size ofapproximately 60 to 20 mesh.

An alternative procedure for preparing drug beads is by blending drugwith one or more pharmaceutically acceptable excipients, such asmicrocrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone,talc, magnesium stearate, a disintegrant, etc., extruding the blend,spheronizing the extrudate, drying and optionally coating to form theimmediate release beads.

5. Formulations for Mucosal and Pulmonary Administration

Active agent(s) and compositions thereof can be formulated for pulmonaryor mucosal administration. The administration can include delivery ofthe composition to the lungs, nasal, oral (sublingual, buccal), vaginal,or rectal mucosa. In a particular embodiment, the composition isformulated for and delivered to the subject sublingually.

In one embodiment, the compounds are formulated for pulmonary delivery,such as intranasal administration or oral inhalation. The respiratorytract is the structure involved in the exchange of gases between theatmosphere and the blood stream. The lungs are branching structuresultimately ending with the alveoli where the exchange of gases occurs.The alveolar surface area is the largest in the respiratory system andis where drug absorption occurs. The alveoli are covered by a thinepithelium without cilia or a mucus blanket and secrete surfactantphospholipids. The respiratory tract encompasses the upper airways,including the oropharynx and larynx, followed by the lower airways,which include the trachea followed by bifurcations into the bronchi andbronchioli. The upper and lower airways are called the conductingairways. The terminal bronchioli then divide into respiratorybronchiole, which then lead to the ultimate respiratory zone, thealveoli, or deep lung. The deep lung, or alveoli, is the primary targetof inhaled therapeutic aerosols for systemic drug delivery.

Pulmonary administration of therapeutic compositions comprised of lowmolecular weight drugs has been observed, for example, beta-androgenicantagonists to treat asthma. Other therapeutic agents that are active inthe lungs have been administered systemically and targeted via pulmonaryabsorption. Nasal delivery is considered to be a promising technique foradministration of therapeutics for the following reasons: the nose has alarge surface area available for drug absorption due to the coverage ofthe epithelial surface by numerous microvilli, the subepithelial layeris highly vascularized, the venous blood from the nose passes directlyinto the systemic circulation and therefore avoids the loss of drug byfirst-pass metabolism in the liver, it offers lower doses, more rapidattainment of therapeutic blood levels, quicker onset of pharmacologicalactivity, fewer side effects, high total blood flow per cm³, porousendothelial basement membrane, and it is easily accessible.

The term aerosol as used herein refers to any preparation of a fine mistof particles, which can be in solution or a suspension, whether or notit is produced using a propellant. Aerosols can be produced usingstandard techniques, such as ultrasonication or high-pressure treatment.

Carriers for pulmonary formulations can be divided into those for drypowder formulations and for administration as solutions. Aerosols forthe delivery of therapeutic agents to the respiratory tract are known inthe art. For administration via the upper respiratory tract, theformulation can be formulated into a solution, e.g., water or isotonicsaline, buffered or un-buffered, or as a suspension, for intranasaladministration as drops or as a spray. Preferably, such solutions orsuspensions are isotonic relative to nasal secretions and of about thesame pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0to pH 7.0. Buffers should be physiologically compatible and include,simply by way of example, phosphate buffers. For example, arepresentative nasal decongestant is described as being buffered to a pHof about 6.2. One skilled in the art can readily determine a suitablesaline content and pH for an innocuous aqueous solution for nasal and/orupper respiratory administration.

Preferably, the aqueous solution is water, physiologically acceptableaqueous solutions containing salts and/or buffers, such as phosphatebuffered saline (PBS), or any other aqueous solution acceptable foradministration to an animal or human. Such solutions are well known to aperson skilled in the art and include, but are not limited to, distilledwater, de-ionized water, pure or ultrapure water, saline,phosphate-buffered saline (PBS). Other suitable aqueous vehiclesinclude, but are not limited to, Ringer's solution and isotonic sodiumchloride. Aqueous suspensions may include suspending agents such ascellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gumtragacanth, and a wetting agent such as lecithin. Suitable preservativesfor aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

In another embodiment, solvents that are low toxicity organic (i.e.nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethylacetate, tetrahydrofuran, ethyl ether, and propanol may be used for theformulations. The solvent is selected based on its ability to readilyaerosolize the formulation. The solvent should not detrimentally reactwith the compounds. An appropriate solvent should be used that dissolvesthe compounds or forms a suspension of the compounds. The solvent shouldbe sufficiently volatile to enable formation of an aerosol of thesolution or suspension. Additional solvents or aerosolizing agents, suchas freons, can be added as desired to increase the volatility of thesolution or suspension.

In one embodiment, compositions may contain minor amounts of polymers,surfactants, or other excipients well known to those of the art. In thiscontext, “minor amounts” means no excipients are present that mightaffect or mediate uptake of the compounds in the lungs and that theexcipients that are present are present in amount that do not adverselyaffect uptake of compounds in the lungs.

Dry lipid powders can be directly dispersed in ethanol because of theirhydrophobic character. For lipids stored in organic solvents such aschloroform, the desired quantity of solution is placed in a vial, andthe chloroform is evaporated under a stream of nitrogen to form a drythin film on the surface of a glass vial. The film swells easily whenreconstituted with ethanol. To fully disperse the lipid molecules in theorganic solvent, the suspension is sonicated. Nonaqueous suspensions oflipids can also be prepared in absolute ethanol using a reusable PARI LCJet+ nebulizer (PARI Respiratory Equipment, Monterey, Calif.).

Dry powder formulations (“DPFs”) with large particle size have improvedflowability characteristics, such as less aggregation, easieraerosolization, and potentially less phagocytosis. Dry powder aerosolsfor inhalation therapy are generally produced with mean diametersprimarily in the range of less than 5 microns, although a preferredrange is between one and ten microns in aerodynamic diameter. Large“carrier” particles (containing no drug) have been co-delivered withtherapeutic aerosols to aid in achieving efficient aerosolization amongother possible benefits.

Polymeric particles may be prepared using single and double emulsionsolvent evaporation, spray drying, solvent extraction, solventevaporation, phase separation, simple and complex coacervation,interfacial polymerization, and other methods well known to those ofordinary skill in the art. Particles may be made using methods formaking microspheres or microcapsules known in the art. The preferredmethods of manufacture are by spray drying and freeze drying, whichentails using a solution containing the surfactant, spraying to formdroplets of the desired size, and removing the solvent.

The particles may be fabricated with the appropriate material, surfaceroughness, diameter and tap density for localized delivery to selectedregions of the respiratory tract such as the deep lung or upper airways.For example, higher density or larger particles may be used for upperairway delivery. Similarly, a mixture of different sized particles,provided with the same or different active agents may be administered totarget different regions of the lung in one administration.

6. Topical and Transdermal Formulations

Transdermal formulations may also be prepared. These will typically begels, ointments, lotions, sprays, or patches, all of which can beprepared using standard technology. Transdermal formulations can includepenetration enhancers.

A “gel” is a colloid in which the dispersed phase has combined with thecontinuous phase to produce a semisolid material, such as jelly.

An “oil” is a composition containing at least 95% wt of a lipophilicsubstance. Examples of lipophilic substances include but are not limitedto naturally occurring and synthetic oils, fats, fatty acids, lecithins,triglycerides and combinations thereof.

A “continuous phase” refers to the liquid in which solids are suspendedor droplets of another liquid are dispersed, and is sometimes called theexternal phase. This also refers to the fluid phase of a colloid withinwhich solid or fluid particles are distributed. If the continuous phaseis water (or another hydrophilic solvent), water-soluble or hydrophilicdrugs will dissolve in the continuous phase (as opposed to beingdispersed). In a multiphase formulation (e.g., an emulsion), thediscreet phase is suspended or dispersed in the continuous phase.

An “emulsion” is a composition containing a mixture of non-misciblecomponents homogenously blended together. In particular embodiments, thenon-miscible components include a lipophilic component and an aqueouscomponent. An emulsion is a preparation of one liquid distributed insmall globules throughout the body of a second liquid. The dispersedliquid is the discontinuous phase, and the dispersion medium is thecontinuous phase. When oil is the dispersed liquid and an aqueoussolution is the continuous phase, it is known as an oil-in-wateremulsion, whereas when water or aqueous solution is the dispersed phaseand oil or oleaginous substance is the continuous phase, it is known asa water-in-oil emulsion. Either or both of the oil phase and the aqueousphase may contain one or more surfactants, emulsifiers, emulsionstabilizers, buffers, and other excipients. Preferred excipients includesurfactants, especially non-ionic surfactants; emulsifying agents,especially emulsifying waxes; and liquid non-volatile non-aqueousmaterials, particularly glycols such as propylene glycol. The oil phasemay contain other oily pharmaceutically approved excipients. Forexample, materials such as hydroxylated castor oil or sesame oil may beused in the oil phase as surfactants or emulsifiers.

“Emollients” are an externally applied agent that softens or soothesskin and are generally known in the art and listed in compendia, such asthe “Handbook of Pharmaceutical Excipients”, 4^(th) Ed., PharmaceuticalPress, 2003. These include, without limitation, almond oil, castor oil,ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esterswax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycolpalmitostearate, glycerin, glycerin monostearate, glyceryl monooleate,isopropyl myristate, isopropyl palmitate, lanolin, lecithin, lightmineral oil, medium-chain triglycerides, mineral oil and lanolinalcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil,starch, stearyl alcohol, sunflower oil, xylitol and combinationsthereof. In one embodiment, the emollients are ethylhexylstearate andethylhexyl palmitate.

“Surfactants” are surface-active agents that lower surface tension andthereby increase the emulsifying, foaming, dispersing, spreading andwetting properties of a product. Suitable non-ionic surfactants includeemulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers,polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters,benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate,poloxamer, povidone and combinations thereof. In one embodiment, thenon-ionic surfactant is stearyl alcohol.

“Emulsifiers” are surface active substances which promote the suspensionof one liquid in another and promote the formation of a stable mixture,or emulsion, of oil and water. Common emulsifiers are: metallic soaps,certain animal and vegetable oils, and various polar compounds. Suitableemulsifiers include acacia, anionic emulsifying wax, calcium stearate,carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol,diethanolamine, ethylene glycol palmitostearate, glycerin monostearate,glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin,hydrous, lanolin alcohols, lecithin, medium-chain triglycerides,methylcellulose, mineral oil and lanolin alcohols, monobasic sodiumphosphate, monoethanolamine, nonionic emulsifying wax, oleic acid,poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylenecastor oil derivatives, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene stearates, propylene glycol alginate, self-emulsifyingglyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate,sorbitan esters, stearic acid, sunflower oil, tragacanth,triethanolamine, xanthan gum and combinations thereof. In oneembodiment, the emulsifier is glycerol stearate.

A “lotion” is a low- to medium-viscosity liquid formulation. A lotioncan contain finely powdered substances that are in soluble in thedispersion medium through the use of suspending agents and dispersingagents. Alternatively, lotions can have as the dispersed phase liquidsubstances that are immiscible with the vehicle and are usuallydispersed by means of emulsifying agents or other suitable stabilizers.In one embodiment, the lotion is in the form of an emulsion having aviscosity of between 100 and 1000 centistokes. The fluidity of lotionspermits rapid and uniform application over a wide surface area. Lotionsare typically intended to dry on the skin leaving a thin coat of theirmedicinal components on the skin's surface.

A “cream” is a viscous liquid or semi-solid emulsion of either the“oil-in-water” or “water-in-oil type”. Creams may contain emulsifyingagents and/or other stabilizing agents. In one embodiment, theformulation is in the form of a cream having a viscosity of greater than1000 centistokes, typically in the range of 20,000-50,000 centistokes.Creams are often time preferred over ointments as they are generallyeasier to spread and easier to remove.

An emulsion is a preparation of one liquid distributed in small globulesthroughout the body of a second liquid. The dispersed liquid is thediscontinuous phase, and the dispersion medium is the continuous phase.When oil is the dispersed liquid and an aqueous solution is thecontinuous phase, it is known as an oil-in-water emulsion, whereas whenwater or aqueous solution is the dispersed phase and oil or oleaginoussubstance is the continuous phase, it is known as a water-in-oilemulsion. The oil phase may consist at least in part of a propellant,such as an HFA propellant. Either or both of the oil phase and theaqueous phase may contain one or more surfactants, emulsifiers, emulsionstabilizers, buffers, and other excipients. Preferred excipients includesurfactants, especially non-ionic surfactants; emulsifying agents,especially emulsifying waxes; and liquid non-volatile non-aqueousmaterials, particularly glycols such as propylene glycol. The oil phasemay contain other oily pharmaceutically approved excipients. Forexample, materials such as hydroxylated castor oil or sesame oil may beused in the oil phase as surfactants or emulsifiers.

A sub-set of emulsions are the self-emulsifying systems. These drugdelivery systems are typically capsules (hard shell or soft shell)comprised of the drug dispersed or dissolved in a mixture ofsurfactant(s) and lipophillic liquids such as oils or other waterimmiscible liquids. When the capsule is exposed to an aqueousenvironment and the outer gelatin shell dissolves, contact between theaqueous medium and the capsule contents instantly generates very smallemulsion droplets. These typically are in the size range of micelles ornanoparticles. No mixing force is required to generate the emulsion asis typically the case in emulsion formulation processes.

The basic difference between a cream and a lotion is the viscosity,which is dependent on the amount/use of various oils and the percentageof water used to prepare the formulations. Creams are typically thickerthan lotions, may have various uses and often one uses more variedoils/butters, depending upon the desired effect upon the skin. In acream formulation, the water-base percentage is about 60-75% and theoil-base is about 20-30% of the total, with the other percentages beingthe emulsifier agent, preservatives and additives for a total of 100%.

An “ointment” is a semisolid preparation containing an ointment base andoptionally one or more active agents. Examples of suitable ointmentbases include hydrocarbon bases (e.g., petrolatum, white petrolatum,yellow ointment, and mineral oil); absorption bases (hydrophilicpetrolatum, anhydrous lanolin, lanolin, and cold cream); water-removablebases (e.g., hydrophilic ointment), and water-soluble bases (e.g.,polyethylene glycol ointments). Pastes typically differ from ointmentsin that they contain a larger percentage of solids. Pastes are typicallymore absorptive and less greasy that ointments prepared with the samecomponents.

A “gel” is a semisolid system containing dispersions of small or largemolecules in a liquid vehicle that is rendered semisolid by the actionof a thickening agent or polymeric material dissolved or suspended inthe liquid vehicle. The liquid may include a lipophilic component, anaqueous component or both. Some emulsions may be gels or otherwiseinclude a gel component. Some gels, however, are not emulsions becausethey do not contain a homogenized blend of immiscible components.

Suitable gelling agents include, but are not limited to, modifiedcelluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose;Carbopol homopolymers and copolymers; and combinations thereof. Suitablesolvents in the liquid vehicle include, but are not limited to, diglycolmonoethyl ether; alklene glycols, such as propylene glycol; dimethylisosorbide; alcohols, such as isopropyl alcohol and ethanol. Thesolvents are typically selected for their ability to dissolve the drug.Other additives, which improve the skin feel and/or emolliency of theformulation, may also be incorporated. Examples of such additivesinclude, but are not limited, isopropyl myristate, ethyl acetate,C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone,capric/caprylic triglycerides, and combinations thereof.

Foams consist of an emulsion in combination with a gaseous propellant.The gaseous propellant consists primarily of hydrofluoroalkanes (HFAs).Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures andadmixtures of these and other HFAs that are currently approved or maybecome approved for medical use are suitable. The propellants preferablyare not hydrocarbon propellant gases which can produce flammable orexplosive vapors during spraying. Furthermore, the compositionspreferably contain no volatile alcohols, which can produce flammable orexplosive vapors during use.

Buffers are used to control pH of a composition. Preferably, the buffersbuffer the composition from a pH of about 4 to a pH of about 7.5, morepreferably from a pH of about 4 to a pH of about 7, and most preferablyfrom a pH of about 5 to a pH of about 7. In a preferred embodiment, thebuffer is triethanolamine.

Preservatives can be used to prevent the growth of fungi andmicroorganisms. Suitable antifungal and antimicrobial agents include,but are not limited to, benzoic acid, butylparaben, ethyl paraben,methyl paraben, propylparaben, sodium benzoate, sodium propionate,benzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,and thimerosal.

Additional agents that can be added to the formulation includepenetration enhancers. In some embodiments, the penetration enhancerincreases the solubility of the drug, improves transdermal delivery ofthe drug across the skin, in particular across the stratum corneum, or acombination thereof. Some penetration enhancers cause dermal irritation,dermal toxicity and dermal allergies. However, the more commonly usedones include urea, (carbonyldiamide), imidurea, N, N-diethylformamide,N-methyl-2-pyrrolidone, 1-dodecal-azacyclopheptane-2-one, calciumthioglycate, 2-pyrrolidone, N,N-diethyl-m-toluamide, oleic acid and itsester derivatives, such as methyl, ethyl, propyl, isopropyl, butyl,vinyl and glycerylmonooleate, sorbitan esters, such as sorbitanmonolaurate and sorbitan monooleate, other fatty acid esters such asisopropyl laurate, isopropyl myristate, isopropyl palmitate, diisopropyladipate, propylene glycol monolaurate, propylene glycol monooleatea andnon-ionic detergents such as BRIJ® 76 (stearyl poly(10 oxyethyleneether), BRIJ® 78 (stearyl poly(20)oxyethylene ether), BRIJ® 96 (oleylpoly(10)oxyethylene ether), and BRIJ® 721 (stearyl poly (21) oxyethyleneether) (ICI Americas Inc. Corp.). Chemical penetrations and methods ofincreasing transdermal drug delivery are described in Inayat, et al.,Tropical Journal of Pharmaceutical Research, 8(2):173-179 (2009) andFox, et al., Molecules, 16:10507-10540 (2011). In some embodiments, thepenetration enhancer is, or includes, an alcohol such ethanol, or othersdisclosed herein or known in the art.

Delivery of drugs by the transdermal route has been known for manyyears.

Advantages of a transdermal drug delivery compared to other types ofmedication delivery such as oral, intravenous, intramuscular, etc.,include avoidance of hepatic first pass metabolism, ability todiscontinue administration by removal of the system, the ability tocontrol drug delivery for a longer time than the usual gastrointestinaltransit of oral dosage form, and the ability to modify the properties ofthe biological barrier to absorption.

Controlled release transdermal devices rely for their effect on deliveryof a known flux of drug to the skin for a prolonged period of time,generally a day, several days, or a week. Two mechanisms are used toregulate the drug flux: either the drug is contained within a drugreservoir, which is separated from the skin of the wearer by a syntheticmembrane, through which the drug diffuses; or the drug is held dissolvedor suspended in a polymer matrix, through which the drug diffuses to theskin. Devices incorporating a reservoir will deliver a steady drug fluxacross the membrane as long as excess undissolved drug remains in thereservoir; matrix or monolithic devices are typically characterized by afalling drug flux with time, as the matrix layers closer to the skin aredepleted of drug. Usually, reservoir patches include a porous membranecovering the reservoir of medication which can control release, whileheat melting thin layers of medication embedded in the polymer matrix(e.g., the adhesive layer), can control release of drug from matrix ormonolithic devices. Accordingly, the active agent can be released from apatch in a controlled fashion without necessarily being in a controlledrelease formulation.

Patches can include a liner which protects the patch during storage andis removed prior to use; drug or drug solution in direct contact withrelease liner; adhesive which serves to adhere the components of thepatch together along with adhering the patch to the skin; one or moremembranes, which can separate other layers, control the release of thedrug from the reservoir and multi-layer patches, etc., and backing whichprotects the patch from the outer environment.

Common types of transdermal patches include, but are not limited to,single-layer drug-in-adhesive patches, wherein the adhesive layercontains the drug and serves to adhere the various layers of the patchtogether, along with the entire system to the skin, but is alsoresponsible for the releasing of the drug; multi-layer drug-in-adhesive,wherein which is similar to a single-layer drug-in-adhesive patch, butcontains multiple layers, for example, a layer for immediate release ofthe drug and another layer for control release of drug from thereservoir; reservoir patches wherein the drug layer is a liquidcompartment containing a drug solution or suspension separated by theadhesive layer; matrix patches, wherein a drug layer of a semisolidmatrix containing a drug solution or suspension which is surrounded andpartially overlaid by the adhesive layer; and vapor patches, wherein anadhesive layer not only serves to adhere the various layers together butalso to release vapor. Methods for making transdermal patches aredescribed in U.S. Pat. Nos. 6,461,644, 6,676,961, 5,985,311, and5,948,433.

In a particularly preferred embodiment, THIP or a derivative thereof, isformulated for transdermal delivery and administered using a transdermalpatch. In some embodiments, the formulation, the patch, or both aredesigned for extended release of the THIP or derivative thereof.

Exemplary symptoms, pharmacologic, and physiologic effects are discussedin more detail below.

III. Methods of Treating Secondary Insomnia

Methods of treating secondary insomnia are provided. The methods caninclude administering to the subject an effective amount of4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a derivativethereof to decrease sleep disruption, increase slow wave sleep (SWS)and/or slow wave activity (SWA), normalize sleep architecture, reducesecondary insomnia, increase non-rapid eye movement (NREM) sleep,increase sleep continuity, enhance delta activity within NREM, increaseor improve total sleep time (TST), increase or improve sleep efficiency,reduce total time awake (TAA), reduce number of awakenings (NWA), reducelatency to persistent sleep (LPS), reduce wake after sleep onset (WASO),or any combination thereof. In preferred embodiments, REM sleep is notsubstantially reduced. In some embodiments, the methods are effective toreduce, delay, or prevent one or more other clinical symptoms of aneurodegenerative disease or central nervous system disease or disorder.

A. Treatment Protocol

It has been discovered that THIP and derivatives thereof can be used totreat secondary insomnia. Secondary insomnia is the symptom or sideeffect of another problem, for example, an emotional, neurological, orother medical or sleep disorder. Accordingly, the subject to be treatedtypically suffers from both insomnia and an underlying disease,disorder, or condition that is causing the insomnia.

Emotional disorders that can cause insomnia include depression, anxiety,and posttraumatic stress disorder. Conditions that cause chronic pain,such as arthritis and headache disorders; conditions that make it hardto breathe, such as asthma and heart failure; an overactive thyroid;gastrointestinal disorders, such as heartburn; stroke; sleep disorders,such as restless legs syndrome and sleep-related breathing problems;menopause and hot flashes; medication for example asthma medicines, suchas theophylline, as well as some allergy and cold medicines, betablockers, and medicines used to treat heart conditions can also causesecondary insomnia. Use of caffeine and other stimulants, tobacco orother nicotine products, and alcohol or other sedatives can also lead tosecondary insomnia.

In a preferred embodiment, the secondary insomnia is caused by aneurological disease or disorder, such as one those described in moredetail below.

1. Sleep Architecture

In some embodiments, the subject has or is at risk for developingreduced slow wave sleep, disrupted sleep architecture, or wouldotherwise benefit from increased slow wave sleep. Therefore, in someembodiments, the compositions are administered in an effective amount toreduce, alleviate, or prevent one or more sleep related symptoms. Inpreferred embodiments, THIP or derivative thereof is administered to thesubject in an effective amount to decrease sleep disruption, increaseslow wave sleep (SWS) and/or slow wave activity (SWA), normalize sleeparchitecture, reduce secondary insomnia, increase non-rapid eye movement(NREM) sleep, increase sleep continuity, enhance delta activity withinNREM, increase or improve total sleep time (TST), increase or improvesleep efficiency, reduce total time awake (TAA), reduce number ofawakenings (NWA), reduce latency to persistent sleep (LPS), reduce wakeafter sleep onset (WASO), or any combination thereof. In preferredembodiments, REM sleep is not substantially reduced.

Sleep is an active process generated and modulated by a complex set ofneural systems located mainly in the hypothalamus, brainstem, andthalamus. Sleep is altered in many neurological diseases due tomechanisms including lesions of the brain areas that control sleep andwakefulness, lesions or diseases that produce pain, reduced mobility,and treatments. Excessive daytime sleepiness (EDS), sleep fragmentation,insomnia, sleep-disordered breathing (SDB), nocturnal behavioralphenomena such as rapid eye movement (REM) sleep behavior disorder ornocturnal seizures, restless legs syndrome, and periodic leg movementsyndrome (PLMS) are common symptoms and findings in neurologicaldisorders (Jennum, et al., “CHAPTER 39: Sleep disorders inneurodegenerative disorders and stroke”, European Handbook ofNeurological Management, Volume 1, 2nd Edition (Ed. Gilhus, et al.)Blackwell Publishing Ltd. 2011). In some cases, sleep disorders precedeand influence the disease course in neurological diseases, particularlythose involving daytime functioning, quality of life, morbidity, andmortality.

Evidence is also emerging that subjects with HD can suffer fromabnormalities in both sleep and in the control of daily or ‘circadian’rhythms (Morton, “HDBuzz Special Feature: Huntington's disease andsleep” HDbuzz.net/115, (ed., Wild), Feb. 6, 2013). Therefore, sleep andcircadian dysfunction are symptoms of HD. Other sleep-related symptomsin patients with Huntington's disease in the diminishment of involuntarymovements tend to diminish during sleep, sleep disturbances, includingdisturbed sleep pattern with an increased sleep onset latency, reducedsleep efficiency, frequent nocturnal awakenings, and more time spentawake with less slow wave sleep. These abnormalities can correlate inpart with the duration of illness, severity of clinical symptoms, anddegree of atrophy of the caudate nucleus. The sleep phenotype ofHuntington's disease may also include insomnia, advanced sleep phase,periodic leg movements, REM sleep behavior disorder (RBD), and reducedREM sleep. Reduced REM sleep may precede chorea, and mutant huntingtinmay exert an effect on REM sleep and motor control during sleep.

Sleep-wake problems are also frequent, although often unrecognized,complications of amyotrophic lateral sclerosis (ALS). Sleep disorderssuch as insomnia, sleep-disordered breathing and restless legs syndromehave all been reported in patients with ALS, despite the limited numberof studies and the small populations investigated so far (Lo Coco, etal., Neurodegenerative Disease Management, 2(3):315-324 (2012)). Theprognosis in ALS is closely related to respiratory muscle strength, andsudden nocturnal death often occurs during sleep. Respiratory indicessuch as low nocturnal oxygen saturation are associated with a poorerprognosis. Patients with diaphragmatic involvement may havesignificantly reduced REM sleep. Patients with dementias often presentcircadian disturbances which have been treated with melatonin and lighttherapy.

Sleep and circadian dysfunction may be caused by other symptoms of theneurodegenerative disease, or may be caused by factors that areindependent of the disease. Sleep and circadian dysfunction can becaused by personal habits, lifestyle or environment, for example,staying up too late, getting up too early, taking drugs that interferewith sleep, and/or over-stimulation due to late-night activities such aswork, television, etc. Sleep and circadian disturbance inneurodegenerative disease patients are likely to contribute to diseasesymptoms that are worsened by sleep deprivation, such as irritabilityand anxiety, and may precede and influence the disease course involvingdaytime functioning, quality of life, morbidity, and mortality. Forexample, sleep disturbances have been reported to gradually worsen withdisease progression in ALS, indicating a relationship between theseverity of disease and the neurodegenerative process. Furthermore,subjects with a neurodegenerative disease may not have the sameneurological reserves to handle sleep deprivation that healthy subjectsrely upon.

Poor sleep can also be a consequence of several disturbances such asanxiety, depression, pain, choking, sialorrhea, fasciculations, cramps,nocturia and the inability to get comfortable and move freely in bed.Sleep disorders may have many reflections on patients includingexcessive daytime somnolence, fatigue, impaired cognition, reducedquality of life and survival (Lo Coco, et al., Neurodegenerative DiseaseManagement, 2(3):315-324 (2012)).

Circadian rhythms and sleep are two different processes, although theterms are often used interchangeably. Circadian rhythms are biologicalprocesses that change roughly every 24 hours. They are orchestrated by asmall part of the brain known as the suprachiasmatic nucleus or SCN,which regulates the body's activities including when to get up and whento go to bed. Sleep is a circadian behavior, but is just one of manycircadian behaviors that are influenced by the SCN. Others include heartrate, hormone secretion, blood pressure and body temperature.

During the night, sleep follows a predictable pattern, moving back andforth between deep restorative sleep (deep sleep) and more alert stages(collective referred to as Non-REM or NREM) and dreaming (REM sleep).Specifically, the sleep cycle includes stages W (wakefulness), N1 (NREM1), N2 (NREM 2), N3 (NREM3), and R (REM). Sleep stages can be identifiedby monitoring a subject's brain electrical activity (e.g., brain waves).The criteria for each stage, and methods for determining the stage of asleeping subject, and profiling a subject's sleep architecture aredescribed in Iber, et al., “The AASM Manual for the Scoring of Sleep andAssociated Events, American Academy of Sleep Medicine”, pg. 1-57 (2007),which is specifically incorporated by reference herein in its entirety.

Together, the stages of REM and non-REM sleep form a complete sleepcycle. Each cycle typically lasts about 90 minutes and repeats four tosix times over the course of a typical night's sleep. A normal adultspends approximately 50% of total sleep time in Stage 2 sleep, 20% inREM sleep, and 30% in the remaining stages, including deep sleep. Forexample, a typical first sleep cycle, N1, is characterized by alow-voltage, mixed-frequency pattern, and may last for about 1 to about10 minutes. The second stage, N2, comes next is characterized by sleepspindles and/or K complexes in the EEG recording. N2 generally lastsabout 10 to about 25 minutes. As N2 sleep progresses, there is a gradualappearance of the high-voltage, slow-wave activity characteristic of N3,the third stage of NREM sleep. This stage, which generally lasts about20 to about 40 minutes, is referred to as “slow-wave,” “delta,” or“deep” sleep. Following the N3 stage of sleep, a series of bodymovements usually signals an “ascent” to lighter NREM sleep stages.Typically, a 5 to 10 minute period of N2 precedes the initial REM sleepepisode. REM sleep episodes, the first of which may last only one tofive minutes, generally become longer through the night. During atypical night, N3 sleep occupies less time in the second cycle than thefirst and may disappear altogether from later cycles. The average lengthof the first NREM-REM sleep cycle is between 70 and 100 minutes; theaverage length of the second and later cycles is about 90 to 120minutes. REM sleep makes up about 20 to 25 percent of total sleep intypical healthy adults (“Natural Patterns of Sleep”healthysleep.med.harvard.edu/healthy/science/what/sleep-patterns-rem-nrem,A resource from the Division of Sleep Medicine at Harvard Medical School(2007)).

The duration of the stages of the sleep cycle alone, or in combinationwith the cycling of the stages can be referred to as a subject's sleeparchitecture. In some embodiments, neurodegenerative disease subjectshave disrupted sleep architecture, for example, an alteration in theduration of one or more sleep cycles, an alternation in the duration ornumber of sleep cycles, or any combination thereof compared to a controlor reference value. A control or reference value in this case can be,for example, an average, normal duration for the stage, or averagenormal duration or number of cycles in subject or subjects that do notsuffer from disrupted or disturbed sleep architecture (e.g., a healthysubject).

Therefore, in some embodiments, THIP or a derivative thereof isadministered to a subject in an effective amount to normalize asubject's sleep architecture, for example, by bringing one or moreaspects of the subject's sleep architecture into closer alignment withthat of a normal subject.

Slow-wave sleep (SWS), often referred to as deep sleep, consists of N3,non-rapid eye movement sleep. The 1968 categorization of the combinedSleep Stages 3-4 was reclassified in 2007 as Stage N3. An epoch (30seconds of sleep) which consists of 20% or more of slow wave (delta)sleep, is now considered to be stage 3 (Gazzaniga, Just the Facts 101,e-Study Guide for: Psychological Science, Content Technologies Inc.,2014). Slow-wave sleep is believed to be important to consolidate newmemories, and sleep deprivation studies with humans indicate that amongother things, an important function of slow-wave sleep may be to allowthe brain to recover from its daily activities.

Rapid eye movement (REM) sleep is a stage of sleep characterized by therapid and random movement of the eyes and can be classified into twocategories: tonic and phasic. Criteria for REM sleep includes rapid eyemovement, low muscle tone and a rapid, low-voltage EEG—features whichcan be identified by polysomnogram. REM sleep typically occupies 20-25%of total sleep, about 90-120 minutes of a night's sleep.

In some embodiments THIP or a derivative thereof is administered to asubject in an effective amount to increase the length of one or more N3stages during a subject's sleep, increase the number of N3 stages duringa subject's sleep, or a combination thereof. In some embodiments, thecompositions increase slow wave sleep by at least 15 minutes, at least30 minutes, at least 45 minutes, at least 60 minutes, at least 75minutes, at least 90 minutes, or at least 120 minutes over the course ofthe sleeping period (e.g., overnight). In some embodiments thecompositions double or more the amount of slow wave sleep in thesubject.

2. Dosage and Administration

The disclosed methods of treating secondary insomnia typically includeadministering to a subject in need thereof an effective amount of THIPor a derivative thereof, preferably is a pharmaceutically acceptablecomposition such as those discussed in more detail above.

The effective amount or therapeutically effective amount is typically adosage sufficient to decrease sleep disruption, increase slow wave sleep(SWS) and/or slow wave activity (SWA), normalize sleep architecture,reduce secondary insomnia, increase non-rapid eye movement (NREM) sleep,increase sleep continuity, enhance delta activity within NREM, increaseor improve total sleep time (TST), increase or improve sleep efficiency,reduce total time awake (TAA), reduce number of awakenings (NWA), reducelatency to persistent sleep (LPS), reduce wake after sleep onset (WASO),or any combination thereof. In preferred embodiments, REM sleep is notsubstantially reduced.

In some embodiment the method reduces or prevents one or moreneuropsychiatric morbidities in a subject with a neurodegenerativedisease or disorder. Therefore, the amount can be effective to treat orprevent one or more symptoms of a neurodegenerative disease or centralnervous system disorder, or to otherwise provide a desired pharmacologicand/or physiologic effect.

The precise dosage will vary according to a variety of factors such assubject-dependent variables (e.g., age, immune system health, clinicalsymptoms etc.). Exemplary dosages, symptoms, pharmacologic, andphysiologic effects are discussed in more detail below.

Studies of the effect of gaboxadol in improving sleep in subjects arediscussed and reviewed in Walsh, et al., Journal of Clinical SleepMedicine, 5(2):527-532 (2009) and Deacon, et al., Sleep, 30(3):281-287(2007). For example, 15 mg of gaboxadol resulted in significantly morestage 4 sleep and SWS (but not stage 3) compared with the placebo group(both p<0.001) in subjects under sleep-restriction (a mean of 21.8minutes more SWS was seen with gaboxadol compared to placebo over foursleep-restriction nights), Walsh, et al., Journal of Clinical SleepMedicine, 5(2):S27-S32 (2009). Gaboxadol also resulted in small butsignificant reductions in stage 1 sleep, REM sleep, and shifts to wakeor stage 1 sleep relative to placebo.

In another dose-response study, 5, 10, or 15 mg gaboxadol wasadministered to 109 healthy subjects in whom habitual sleep time wasadvanced by 4 hours to produce transient sleep disruption (Walsh, etal., Sleep, 30:593-602 (2007)). The study results show that gaboxadolproduced a dose-related increase of approximately 5 to 22 minutes in SWScompared with placebo. TST was significantly increased by approximately30 minutes (p<0.001) and WASO was reduced by approximately 17-20 minutes(p<0.05) compared to placebo at all dosages. Subjective measures ofsleep quality also improved with gaboxadol relative to placebo.

A dose-related study of 40 primary insomnia subjects administered 10 and20 mg of gaboxadol also reported an increase in SWS compared withplacebo (10 mg: p<0.01; 20 mg: p<0.001) (Lundahl, et al.,Psychopharmacology (Berl), 195:139-46 (2007). Gaboxadol at dosage of 20mg significantly reduced WASO (p<0.01), and both doses of gaboxadolsignificantly reduced NASO (p<0.001). Gaboxadol at a dosage of 20 mgalso significantly increased TST (p<0.05).

In another study of the effect of gaboxadol on 26 patients with primaryinsomnia, 15 mg was shown to enhance SWS in a study withoutsignificantly affecting stage 1, stage 2, or REM sleep (Deacon, et al.,Sleep, 30(3):281-287 (2007)). Gaboxadol at dosages 5 mg and 15 mgsignificantly improved TST (p<0.05). The results also indicate that WASOimproved, however, statistical significance was only achieved with the 5mg dose. A gaboxadol dosage of 15 mg also significantly reduced latencyto persistent sleep (p<0.05).

Furthermore, in pre-clinical studies and in studies in healthy young andelderly individuals, gaboxadol was found to increase NREM sleep, sleepcontinuity, enhances delta activity within NREM sleep, and increaseSWS/SWA without suppressing REM sleep (Lancel, et al., Neuroreport,7:2241-5 (1996), Lancel, et al., Sleep, 20:1099-104 (1997), Faulhaber,et al., Psychopharmacology (Berl), 130:285-91 (1997), Lancel, Sleep;22:33-42 (1999), Lancel, et al., Am J Physiol Endocrinol Metab,281:E130-7 (2001), Mathias, et al., Psychopharmacology (Berl),157:299-304 (2001), Mathias, et al., Neuropsychopharmacology, 30:833-41(2005)).

In preferred embodiments, THIP or derivative thereof is administered toa subject in an effective amount to increase slow wave sleep in thesubject.

Particularly preferred embodiments include formulations for extendedrelease. For example, the formulation can be suitable for administrationonce daily or less. In some embodiments, the composition is onlyadministered to the subject once every 24-48 hours. In some embodiments,THIP or a derivative thereof is administered at night before sleep. Inother embodiments, THIP or a derivative thereof is administered inmorning, or at least several hours before sleep.

The timing of the administration of the composition will depend on theformulation and/or route of administration used. In some embodiments,administration of the composition will be given as a long-term treatmentregimen whereby pharmacokinetic steady state conditions will be reached.Medication for peroral or parenteral administration may also be given inimmediate relation to a particular sleeping period, for instance 10minutes to 3 hours prior to the onset of sleep. Thus, the compositioncan be administered in immediate relation to a particular sleepingperiod, for example, from 5 minutes to 5 hours prior to onset of sleep,10 minutes to 3 hours prior to the onset of sleep.

A preferred route of administration is transdermal, for example, atransdermal patch or gel that is contacted with the skin of the subject.In a particular embodiment, the transdermal formulation is administeredto a subject prior to the subject going to sleep (e.g., at night) usinga transdermal patch. In another particular embodiment, the transdermalformulation is administered to a subject in the morning using atransdermal patch. As discussed in more detail below, in some methods asubject with a neurodegenerative disease or central nervous systemdisorder is transdermally administered an amount of THIP or a derivativethereof effective to decrease sleep disruption or increase slow wavesleep in the subject.

In general, by way of example only, dosage forms useful in the disclosedmethods can include doses in the range of 0.1 to 1,000 mg, 1 to 200 mg,5 to 175 mg, 7.5 to 150 mg, or 10 to 125 mg, or 12.5 to 150 mg, or 15 to125 mg, or 17.5 to 100 mg, or 20 to 75 mg, or 22.5 to 60 mg, or 25 to 50mg, with doses of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg,40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 75 mg, and 100 mg being specificexamples of preferred doses. Typically, such dosages are administeredonce, twice, or three times daily, or every other day to a human.

A typical oral dose form preferably includes from about 2.5 mg to about30 mg THIP. Preferably, the THIP is in a crystalline form. Furtherembodiments of the medicament comprises an effective amount of THIP from2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18mg, or 18 mg to 20 mg, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg,17.5 mg, or 20 mg. A typical embodiment is about 5 mg to about 20 mg ofcrystalline THIP, such as the hydrochloride of THIP. Typically, suchdosages are administered once, twice, or three times daily, or everyother day to a human. In some embodiments, the total amount administeredto a subject in 24 hour period is 1 mg to 50 mg. In some embodiments,the subject is started at a low dose and the dosage is escalated in thedrug is well tolerated in the subject.

When given orally in healthy subjects, gaboxadol is rapidly absorbed(tmax of 30-60 min) and eliminated (t½ of 1.5 h) (Deacon, et al., Sleep,30(3):281-287 (2007)). More than 95% of the dose is excreted in theurine, mostly unchanged, with a glucoronide conjugate being the onlymetabolite formed in significant amounts.

In some embodiments, the effect of the composition on a subject iscompared to a control. For example, the effect of the composition on aparticular symptom, pharmacologic, or physiologic indicator can becompared to an untreated subject, or the condition of the subject priorto treatment. In some embodiments, the symptom, pharmacologic, orphysiologic indicator is measured in a subject prior to treatment, andagain one or more times after treatment is initiated. In someembodiments, the control is a reference level, or average determinedbased on measuring the symptom, pharmacologic, or physiologic indicatorin one or more subjects that do not have the disease or condition to betreated (e.g., healthy subjects). In some embodiments, the effect of thetreatment is compared to a conventional treatment that is known the art,such as one of those discussed herein.

3. Intravenous Delivery

In some embodiments, the composition is administered by intravenousinjection or infusion. When administered orally, transport of gaboxadolfrom the intestine into the portal circulation takes place via thetransporter PAT1. Because the amino acid substrates of the PAT1transporter, including but not limited to, proline, tryptophan, alanine,and glycine, are present in food, their presence during oraladministration can influence absorption of the gaboxadol. Morespecifically, PAT1 inhibitors such as L-tryptophan can decrease theabsorption rate constant, k_(a), and C_(max), and increase T_(max) ofgaboxadol (see, for example, Larsen, et al., Br. J. Pharmacol.,157(8):1380-1389 (2009) and WO 2009/056146). Therefore, it is believedthat intravenous administration can improve control of plasma levels(and brain levels) over oral administration due to significantvariability of gaboxadol uptake via the oral route. Furthermore, highpeak concentrations of gaboxadol in predisposed individuals leads tohallucinations and has resulted in discontinuation of the drug'sadministration to some subjects. Intravenous delivery provides theability to titrate dose which ensures that high peak C_(max) is notobserved, and helps avoid this potential adverse event.

In some embodiments, the use of intravenous administration allows forthe composition to be delivered in a lower dosage than, for example,when it is delivered orally. A preferred rate for IV delivery is 0.001mg/kg per hour to 1 mg/kg per hour. The treatment can be administeredfor the course of minutes, hours, or days. Dosages, including totallydaily dosages, are discussed above. In particular embodiments, a singletreatment includes intravenously administering to a subject in needthereof a total of between about 0.001 mg and about 30 mg of THIP orderivative thereof. In some embodiments, the administration is repeatedat least once with an interval of about 3 to about 5 hours. In someembodiments, the administration is repeated at least six times in aperiod of twenty-four hours. In various embodiments, the administrationis repeated three to eight times (e.g., three times, four times, fivetimes, six times, seven times, or eight times) in a period oftwenty-four hours and between about 0.001 mg and about 30 mg of THIP orderivative thereof is delivered over the twenty-four hour period. Dosageregimens are also discussed above. For example, in some embodiments, asingle treatment can be repeated 1, 2, 3, 4, 5, 6, 7, or more days,weeks, or months apart. Intravenous administration increases the easewith which side effects associated with dosage escalation can bemonitored, improves the ability to control plasma concentrations, andincludes the ability to titrate dosage. Accordingly, in someembodiments, the intravenous dosage regimen includes escalation of thedosage from 0.001 mg to about 30 mg of THIP or derivative thereof in atwenty-four hour period, until the dosage is effective to treat thesubject, and preferably without inducing undesirable side effects.Intravenous protocols can also be adapted from those known in the art.See, for example, U.S. Published Application 2009/0143474.

B. Conditions, Symptoms, Subjects, and Diseases to be Treated

The disclosed compositions are typically administered to subjects with aneurodegenerative disease or disorder or central nervous systemdisorder, particularly those leading to secondary insomnia in thesubject. Neurodegeneration refers to the progressive loss of structureor function of neurons, including death of neurons. Exemplary diseasesand disorders are provided below. In some embodiments, the compositionsare administered to subjects that do not have a neurodegenerativedisease or disorder.

Neurodegeneration, and diseases and disorders thereof, can be caused bya genetic mutation or mutations; protein misfolding; intracellularmechanisms such as dysregulated protein degradation pathways, membranedamage, mitochondrial dysfunction, or defects in axonal transport;defects in programmed cell death mechanisms including apoptosis,autophagy, cytoplasmic cell death; and combinations thereof. Morespecific mechanisms common to neurodegenerative disorders include, forexample, oxidative stress, mitochondrial dysfunction, excitotoxicity,inflammatory changes, iron accumulation, and/or protein aggregation.

1. Symptoms

In some embodiments, the disclosed compositions are administered to asubject in need thereof in an effective amount to reduce or prevent oneor more molecular or clinical symptoms of a neurodegenerative disease,or one or more mechanisms that cause neurodegeneration. Symptoms ofneurodegenerative diseases are known in the art and vary from disease todisease. In some embodiments, the disease exhibits or is characterizedby one or any combination of the following symptoms or diseases: stress,anxiety, seasonal depression, insomnia and tiredness, schizophrenia,panic attacks, melancholy, dysfunction in the regulation of appetite,insomnia, psychotic problems, epilepsy, senile dementia, variousdisorders resulting from normal or pathological aging, migraine, memoryloss, disorders of cerebral circulation, cardiovascular pathologies,pathologies of the digestive system, fatigue due to appetite disorders,obesity, pain, psychotic disorders, diabetes, senile dementia, or sexualdysfunction. In some embodiments, the subject does not exhibit one ormore of the preceding symptoms.

In some embodiments, the subject has been medically diagnosed as havinga neurodegenerative disease or a condition in need of neuroprotection byexhibiting clinical (e.g., physical) symptoms of the disease. Asdiscussed above, in some patients the appearance of sleep-relateddisorder precedes a clinical diagnosis of a disease. Therefore, in someembodiments, the compounds or compositions disclosed herein areadministered prior to a clinical diagnosis of a disease or condition. Insome embodiments, a genetic test indicates that the subject has one ormore genetic mutations associated with a neurodegenerative disease orcentral nervous system disorder.

Neurodegenerative diseases are typically more common in agedindividuals. Therefore in some embodiments, the subject is greater the40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 years in age.

2. Diseases to be Treated

The methods disclosed herein can be used to treat subjects with aneurodegenerative disease or disorder. Exemplary neurodegenerativediseases include, but are not limited to, Parkinson's Disease (PD) andPD-related disorders, Huntington's Disease (HD), Amyotrophic LateralSclerosis (ALS), Alzheimer's Disease (AD) and other dementias, PrionDiseases such as Creutzfeldt-Jakob Disease, Corticobasal Degeneration,Frontotemporal Dementia, HIV-Related Cognitive Impairment, MildCognitive Impairment, Motor Neuron Diseases (MND), SpinocerebellarAtaxia (SCA), Spinal Muscular Atrophy (SMA), Friedreich's Ataxia, LewyBody Disease, Alpers' Disease, Batten Disease,Cerebro-Oculo-Facio-Skeletal Syndrome, Corticobasal Degeneration,Gerstmann-Straussler-Scheinker Disease, Kuru, Leigh's Disease, MonomelicAmyotrophy, Multiple System Atrophy, Multiple System Atrophy WithOrthostatic Hypotension (Shy-Drager Syndrome), Multiple Sclerosis (MS),Neurodegeneration with Brain Iron Accumulation, Opsoclonus Myoclonus,Posterior Cortical Atrophy, Primary Progressive Aphasia, ProgressiveSupranuclear Palsy, Vascular Dementia, Progressive MultifocalLeukoencephalopathy, Dementia with Lewy Bodies, Lacunar syndromes,Hydrocephalus, Wernicke-Korsakoff's syndrome, post-encephaliticdementia, cancer and chemotherapy-associated cognitive impairment anddementia, and depression-induced dementia and pseudodementia.

In some embodiments, the subject has a central nervous system disorderor is in need of neuroprotection. Exemplary conditions and/or subjectsinclude, but are not limited to, subjects having had, subjects with, orsubjects likely to develop or suffer from a stroke, a traumatic braininjury, a spinal cord injury, Post Traumatic Stress syndrome, or acombination thereof.

a. Huntington's Disease

The methods disclosed herein can be used to treat subjects withHuntington's disease. Huntington's disease (HD) is a neurodegenerativegenetic disorder that affects muscle coordination and leads to cognitivedecline and psychiatric problems. The chronic pathology in HD leads tonumerous associated troubles including cognitive dysfunctions, morespecifically dysfunction in thought and mental representations, changesin reasoning, in judgment. HD is caused by an autosomal dominantmutation in either of an individual's two copies of the Huntingtin (HTT)gene. Part of this gene is a repeated section called a trinucleotiderepeat, which varies in length between individuals and may change lengthbetween generations. If the repeat is present in a healthy gene, adynamic mutation may increase the repeat count and result in a defectivegene. When the length of this repeated section reaches a certainthreshold, it produces an altered form of the protein, called mutantHuntingtin protein (mHtt). The differing functions of these proteins arethe cause of pathological changes which in turn cause the diseasesymptoms. The Huntington's disease mutation is genetically dominant andalmost fully penetrant. Mutation of either of a person's HTT genes cancause the disease. Physical symptoms of Huntington's disease can beginat any age from infancy to old age, but usually begin between 35 and 44years of age (Walker, et al., Lancet, 369(9557):218-28 (2007)).

In some embodiments, the subject exhibits one or more of the HD clinicalsymptoms, one or more HD molecular symptoms, or a combination thereof,such as those discussed herein and elsewhere. Clinical symptoms of HDare known in the art and include behavioral disturbances including, butnot limited to, hallucinations, irritability, moodiness, restlessness,fidgeting, paranoia, psychosis, suicidal thoughts, and suicide attempts;abnormal and/or unusual movements including, but not limited to, chorea,facial movements such as grimaces, head turning to shift eye position,quick, sudden, sometimes wild jerking movements of the arms, legs, face,and other body parts, slow, uncontrolled movements, unsteady gait, smallunintentionally initiated or uncompleted motions, and lack ofcoordination; cognitive impairment and/or dementia-related symptomsincluding, but not limited to, disorientation and/or confusion, loss ofjudgment, loss of memory, personality changes, and speech changes; andother symptoms including anxiety, stress, tension, difficultyswallowing, speech impairment, rigidity, slow movements, tremor,malnutrition, and weight loss. Neuropsychiatric features are a corecomponent of the disease.

Mutant Huntingtin is expressed throughout the body and associated withabnormalities in peripheral tissues that are directly caused by suchexpression outside the brain. These abnormalities include muscleatrophy, cardiac failure, impaired glucose tolerance, weight loss,osteoporosis and testicular atrophy.

A number of studies have examined the prevalence of the myriad ofsymptoms in subjects with Huntington's disease. Shiwach, Acta PsychiatrScand, 90(4):241-6 (1994) reports the results of a retrospective studyof 110 patients with Huntington disease in 30 families. The study foundthe minimal lifetime prevalence of depression to be 39%. The frequencyof symptomatic schizophrenia was 9%, and significant personality changewas found in 72% of the sample. The age at onset was highly variable.Some showed signs in the first decade and some not until over 60 yearsof age.

Rosenberg, et al., J Med Genet., 32(8):600-4 (1995) describes adouble-blind study on 33 persons at risk for HD who had applied forgenetic testing. Significantly inferior cognitive functioning wasdisclosed in gene carriers by a battery of neuropsychologic testscovering attentional, visuospatial, learning, memory, and planningfunctions. Primarily, attentional, learning, and planning functions wereaffected.

Bamford, et al., Neurology, 45(10):1867-73 (1995) reports a prospectiveanalysis of neuropsychologic performance and CT scans of 60 individualswith Huntington's disease. The study found that psychomotor skillsshowed the most significant consistent decline among cognitive functionsassessed.

Marshall, et al., Arch Neurol., 64(1):116-21 (2007) reports a studycomparing psychiatric manifestations among 29 HD mutation carriers withno clinical symptoms, 20 HD mutation carriers with mild motor symptoms,34 manifesting HD patients, and 171 nonmutation controls. The mild motorsymptoms group and the manifesting HD group showed significantly higherscores for obsessive-compulsive behavior, interpersonal sensitivity,anxiety, paranoia, and psychoticism compared to the nonmutation controlgroup. The mutation carriers without symptoms had higher scores foranxiety, paranoid ideation, and psychoticism compared to the nonmutationcontrol group. The results indicated that individuals in the preclinicalstage of HD exhibit specific psychiatric symptoms, and that additionalsymptoms may manifest later in the disease course. Suicidal ideation isa frequent finding in Huntington disease and physicians should be awareof increased suicide risk both in asymptomatic at-risk patients andsymptomatic patients (Walker, et al., Lancet, 369(9557):218-28 (2007)).

The mechanisms underlying HD are explored in Wang, et al., Journal ofNeuroscience, 31(41):14496-14507 (2011), which is discussed in moredetail below. The study shows that mutant huntingtin (htt)-mediatedtoxicity in cells, mice, and humans is associated with loss of the type1 melatonin receptor (MT1). High levels of MT1 receptor were found inmitochondria from the brains of wild-type mice but much less in brainsfrom HD mice, melatonin inhibited mutant htt-induced caspase activationand preserved MT1 receptor expression. Therefore, in some embodiments,the compounds and compositions disclosed herein are administered to asubject with HD in an effective amount to treat one or more molecularsymptoms of HD, for example, to reduce, delay or inhibit mutanthtt-induced caspase activation; to reduce or prevent loss of MT1receptor expression, particularly in the mitochondria of cell of thesubject; or a combination thereof.

In some embodiments, the subject exhibits one or more symptoms discussedherein, but does not exhibit all of the symptoms. Therefore, in someembodiments, the subject does not have one or more of the symptomsdisclosed herein or elsewhere.

In some embodiments, the subject has been medically diagnosed as havingHD by exhibiting clinical (e.g., physical) symptoms of the disease.Excessive unintentional movements of any part of the body are often thefirst clinical symptoms. If these are abrupt and have random timing anddistribution, they suggest a diagnosis of HD. Cognitive or psychiatricsymptoms are rarely the first diagnosed and are most typically onlyrecognized in hindsight or when they develop further. Diseaseprogression can be measured using the unified Huntington's diseaserating scale which provides an overall rating system based on motor,behavioral, cognitive, and functional assessments (Huntington StudyGroup, Movement Disorders, 11(2):136-142 (1996)).

Medical imaging, such as computerized tomography (CT) and magneticresonance imaging (MRI), and functional neuroimaging techniques, such asfMRI and PET, can supplement analysis of physical symptoms but aretypically not diagnostic alone.

Genetic testing can be used to confirm a physical diagnosis if there isno family history of HD. Even before the onset of symptoms, genetictesting can confirm if an individual or embryo carries an expanded copyof the trinucleotide repeat in the HTT gene that causes the disease. TheU.S. government sponsored genetic disease compendium, the OnlineMendelian Inheritance in Man (OMIM) database, gives HD a phenotypenumber #143100. The gene/locus is huntingtin (HTT), and is located onChromosome 4p16.3 with the Gene/Locus MIM number of 613004. Assignmentof the 143100 number to the OMIM entry is because Huntington disease(HD) is a monogenetic disorder caused by an expanded trinucleotiderepeat (CAG)n, encoding glutamine, in the gene encoding huntingtin (HTT;613004) on chromosome 4p16.3. The genetic test for HD consists of ablood test which counts the numbers of CAG repeats in each of the HTTalleles.

Cutoffs for genetic testing are given as follows according to DeDie-Smulders, et al., Human Reproduction Update, 19(3):304-315 (2013).

40 or more CAG repeats: full penetrance allele (FPA). A “positive test”or “positive result” generally refers to this case. A person who testspositive for the disease will develop HD sometime within their lifetime,provided he or she lives long enough for the disease to appear.

36 to 39 repeats: incomplete or reduced penetrance allele (RPA). It maycause symptoms, usually later in the adult life. There is a maximum riskof 60% that a person with an RPA will be symptomatic at the age of 65years, and a 70% risk of being symptomatic at the age of 75 years.

27 to 35 repeats: intermediate allele (IA), or large normal allele. Itis not associated with symptomatic disease in the tested individual, butmay expand upon further inheritance to give symptoms in offspring.

26 or less repeats: Not associated with HD.

A positive result is considered different than a clinical diagnosis,since it may be obtained decades before the symptoms begin. The test cantell a person who originally had a 50 percent chance of inheriting thedisease if their risk goes up to 100 percent or is eliminated.

Elsewhere, the range of repeat numbers for normal individual is 9 to 36,and 37 or greater in HD individuals (Duyao et al., Nat Genet.,4(4):387-92 (1993)).

Therefore, in some embodiments, the subject has a “positive result”, oris determined to have incomplete or reduced penetrance allele (RPA), oris determined to have intermediate allele (IA), or large normal alleleby genetic testing, but does not exhibit any of the clinical symptoms,or the clinical symptoms are too mild for an affirmative medicaldiagnosis. In a particular embodiment, the subject has a “positiveresult” but does not exhibit any of the clinical symptoms, or theclinical symptoms are too mild for an affirmative medical diagnosis.

Accordingly, in some embodiments, the compounds or compositionsdisclosed herein are administered prior to a clinical diagnosis of HD.

b. Parkinson's Disease

In a particular embodiment, the disclosed compositions are used to treata subject with Parkinson's disease or suffering from parkinsonism orparkinson's syndrome. PD is a degenerative disorder of the centralnervous system. In some embodiments, the subject exhibits one or more ofthe PD clinical symptoms, one or more PD molecular symptoms, or acombination thereof, such as those discussed herein and elsewhere.Symptoms of PD are well known in the art and reviewed in Jankovic, etal., J. Neurol. Neurosurg. Psychiatr., 79(4): 368-76 (2007). The motorsymptoms of Parkinson's disease result from the death ofdopamine-generating cells in the substantia nigra, a region of themidbrain. The cause of the cell death remains unknown. Early in thecourse of the disease, the most obvious symptoms are movement-relatedand include, but are not limited to, shaking, rigidity, slowness ofmovement and difficulty with walking and gait. In particular, four motorsymptoms considered hallmarks of PD are tremor, rigidity, slowness ofmovement, and postural instability. The main motor symptoms arecollectively called parkinsonism, or a “parkinsonian syndrome”.

Later, thinking and behavioral problems may arise and can range frommild to severe, with dementia commonly occurring in the advanced stagesof the disease, whereas depression is the most common psychiatricsymptom. Other common neuropsychiatric disturbances include disorders ofspeech, cognition, mood, behavior, and thought. Cognitive disturbances,which can occur in the initial stages of the disease and sometimes priorto diagnosis, include executive dysfunction, which can include problemswith planning, cognitive flexibility, abstract thinking, ruleacquisition, initiating appropriate actions and inhibiting inappropriateactions, and selecting relevant sensory information; fluctuations inattention and slowed cognitive speed; and memory loss.

Other symptoms include sensory, sleep and emotional problems. In fact,disturbances of sleep and wake are among the most common and disablingnon-motor manifestations of PD, affecting as many as 90% of patients(Videnovic, et al., JAMA Neurol. doi:10.1001/jamaneurol.2013.6239,published online February 24, (2014)).

A physician's diagnosis of PD typically comes from a combination ofmedical history and neurological examination. Brain scans of people withPD typically look normal, but can be used to rule out disorders thatcould give rise to similar symptoms. Although no lab test exists for PD,medical organizations have created diagnostic criteria to facilitate andstandardize the diagnostic process. See, for example, the UK Parkinson'sDisease Society Brain Bank, the U.S. National Institute of NeurologicalDisorders and Stroke, and the PD Society Brain Bank which all providecriteria for diagnosing PD.

Parkinson's disease is more common in older people, with most casesoccurring after the age of 50. There is no cure for PD, and the diseaseis most typically managed using one or a combination of levodopa(usually combined with a dopa decarboxylase inhibitor or COMTinhibitor), dopamine agonists and MAO-B inhibitors. Other common agentsinclude amantadine and anticholinergics for treating motor symptoms,clozapine for treating psychosis, cholinesterase inhibitors for treatingdementia, and modafinil for treating daytime sleepiness. Surgery anddeep brain stimulation can be used, most typically when drugs are nolonger effective. Gene therapies, stem cell transplants, neuroprotectiveagents, are also being developed as treatment options for PD.

In some embodiments, the subject exhibits one or more of the PD clinicalsymptoms, one or more ALS molecular symptoms, or a combination thereof,such as those discussed herein and elsewhere. In some embodiments, thesubject exhibits one or more symptoms discussed herein, but does notexhibit all of the symptoms. Therefore, in some embodiments, the subjectdoes not have one or more of the symptoms disclosed herein or elsewhere.

In some embodiments, the subject has been medically diagnosed as havingPD by exhibiting clinical (e.g., physical) symptoms of the disease. Insome embodiments, the subject exhibits one or more symptoms discussedherein, but does not exhibit all of the symptoms. Therefore, in someembodiments, the subject does not have one or more of the symptomsdisclosed herein or elsewhere.

In some embodiments, the subject has been medically diagnosed as havingPD by exhibiting clinical (e.g., physical) symptoms of the disease. Insome patients the appearance of a sleep-related disorder precedes aclinical diagnosis of PD. Therefore, in some embodiments, the compoundsor compositions disclosed herein are administered prior to a clinicaldiagnosis of PD.

c. Amyotrophic Lateral Sclerosis

The methods disclosed herein can be used to treat a subject withamyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is afatal motor neuron disease, affecting both the first and second ordermotor neurons. The progression of ALS is characterized by a degenerationof motor neurons associated with a demyelination in the anterior horn ofthe spinal cord. The etiology is only partially understood. Of the 5-10%familial cases, 20% carry a mutation of the superoxide dismutase 1(SOD1) gene. Such a mutation is also present in 5% of the sporadic cases(Rowland, et al., New Engl J Med, 44:1688-1700 (2001)). Three to fourpercent 3%-4% of familial cases are due to pathogenic variants in eitherthe TDP-43 or FUS gene (Mackenzie, et al., Lancet Neurol., 9:995-1007(2010)).

In some embodiments, the subject exhibits one or more of the ALSclinical symptoms, one or more ALS molecular symptoms, or a combinationthereof, such as those discussed herein and elsewhere. Clinical symptomsof ALS are known in the art. For example, the earliest symptoms of ALSare typically weakness and/or muscle atrophy. Other early symptomsinclude trouble swallowing, cramping, or stiffness of affected muscles;muscle weakness affecting an arm or a leg; and/or slurred and nasalspeech, and in some cases dementia.

To be diagnosed with ALS, a patient must have signs and symptoms of bothupper and lower motor neuron damage that cannot be attributed to othercauses. The diagnosis depends on progressive degeneration of upper (UMN)and lower (LMN) motor neurons findings by history and examination and isaccurate 95% of the time when made by an experienced clinician (Gordon,Aging and Disease, 4(5):295-310 (2013)). Electromyography can be used toconfirm widespread lower motor neuron disease and exclude other diseasessuch as multifocal motor neuropathy with conduction block. Brain andspinal MRI rule out conditions that affect the UMN, including cervicalspondylosis. Occasionally the brain MRI shows bilateral signal changeswithin the corticospinal tracts, a finding that is pathognomonic of ALS.The El Escorial criteria help standardize diagnosis for clinicalresearch studies (Brooks, et al., Amyotroph Lateral Scler Other MotorNeuron Disord, 1:293-299 (2000)).

Over time, patients experience increasing difficulty moving, swallowing(dysphagia), and speaking or forming words (dysarthria). Symptoms ofupper motor neuron involvement include tight and stiff muscles(spasticity) and exaggerated reflexes (hyperreflexia) including anoveractive gag reflex. An abnormal reflex commonly called Babinski'ssign also indicates upper motor neuron damage. Symptoms of lower motorneuron degeneration include muscle weakness and atrophy, muscle cramps,and fleeting twitches of muscles that can be seen under the skin(fasciculations). Degeneration of bulbar upper motor neurons can causeexaggeration of motor expressions of emotion.

Progression is subject-specific, however, eventually most patients arenot able to walk or use their hands and arms. They also lose the abilityto speak and swallow their food, and most end on a portable ventilator.The rate of progression can be measured using an outcome measure calledthe “ALS Functional Rating Scale Revised (ALSFRS-R)”, a 12-iteminstrument administered as a clinical interview or patient-reportedquestionnaire that produces a score between 48 (normal function) and 0(severe disability).

A survey-based study amongst clinicians showed that they rated a 20%change in the slope of the ALSFRS-R would be clinically meaningful(Castrillo-Viguera, et al., Amyotroph Lateral Scler, 11(1-2):178-80(2010)). Therefore, the composition can be administered to a subject anamount effective to change in the slope of the ALSFRS-R of a subject 1%,5%, 10%, 15%, 20%, or more.

In some embodiments, the ALSFRS-R score of the subject is taken priorto, and one or more after initiation of treatment. In some embodiments,the ALSFRS-R score takes day, weeks, months, or more to improve.

In some embodiments, the subject exhibits one or more of the ALSclinical symptoms, one or more ALS molecular symptoms, or a combinationthereof, such as those discussed herein and elsewhere. In someembodiments, the subject exhibits one or more symptoms discussed herein,but does not exhibit all of the symptoms. Therefore, in someembodiments, the subject does not have one or more of the symptomsdisclosed herein or elsewhere.

In some embodiments, the subject has been medically diagnosed as havingALS by exhibiting clinical (e.g., physical) symptoms of the disease. Insome embodiments, the subject exhibits one or more symptoms discussedherein, but does not exhibit all of the symptoms. Therefore, in someembodiments, the subject does not have one or more of the symptomsdisclosed herein or elsewhere.

In some embodiments, the subject has been medically diagnosed as havingALS by exhibiting clinical (e.g., physical) symptoms of the disease. Insome patients the appearance of sleep-related disorder precedes aclinical diagnosis of ALS. Therefore, in some embodiments, the compoundsor compositions disclosed herein are administered prior to a clinicaldiagnosis of ALS. In some embodiments, a genetic test indicates that thesubject has one or more genetic mutations associated with ALS.

d. Alzheimer's Disease

The methods disclosed herein can be used to treat a subject withAlzheimer's disease. Alzheimer's disease (AD) is the most common form ofdementia. Although the cause and progression of AD are not entirelyunderstood, research indicates plaques and tangles in the brain play apathophysiological role. Current treatments only help with the symptomsof the disease and there are no available treatments that stop orreverse the progression of the disease.

In some embodiments, the subject exhibits one or more of the AD clinicalsymptoms, one or more AD molecular symptoms, or a combination thereof,such as those discussed herein and elsewhere. Clinical symptoms of ADare known in the art. Although Alzheimer's disease develops differentlyfor every individual, there are many common symptoms. Early symptoms areoften mistakenly thought to be “age-related” concerns, or manifestationsof stress. One of the most common early symptoms is short term memoryloss. Moderate stage symptoms can include, for example, increased memoryloss and confusion, problems recognizing family and friends,continuously repeating stories, favorite wants, or motions, difficultydoing things that have multiple steps, like getting dressed, and/or lackof concern for hygiene and appearance. Severe stage symptoms caninclude, for example, inability to recognize oneself or family,inability to communicate, lack of control over bowel and bladder,groaning, moaning, or grunting, and/or needing help with all activitiesof daily living. Other common symptoms can include confusion,irritability, aggression, mood swings, trouble with language, andlong-term memory loss. Gradually, bodily functions are lost, ultimatelyleading to death.

When AD is suspected, the diagnosis is usually confirmed with tests thatevaluate behavior and thinking abilities (e.g., cognitive testing),often followed by a brain scan if available. Assessment of intellectualfunctioning including memory testing and neuropsychological tests suchas the mini-mental state examination (MMSE) are widely used to evaluatethe cognitive impairments needed for diagnosis (Waldemar, et al., Eur JNeurol. 14(1):e1-26 (2007)). Neurological examination in early AD willusually provide normal results, except for obvious cognitive impairment,which may not differ from that resulting from other diseases processes,including other causes of dementia.

Examination of brain tissue can lead to a definitive diagnosis. ADdevelops for an unknown and variable amount of time before becomingfully apparent, and it can progress undiagnosed for years.

In some embodiments, the subject exhibits one or more of the AD clinicalsymptoms, one or more ALS molecular symptoms, or a combination thereof,such as those discussed herein and elsewhere. In some embodiments, thesubject exhibits one or more symptoms discussed herein, but does notexhibit all of the symptoms. Therefore, in some embodiments, the subjectdoes not have one or more of the symptoms disclosed herein or elsewhere.

In some embodiments, the subject has been medically diagnosed as havingAD by exhibiting clinical (e.g., physical) symptoms of the disease. Insome embodiments, the subject exhibits one or more symptoms discussedherein, but does not exhibit all of the symptoms. Therefore, in someembodiments, the subject does not have one or more of the symptomsdisclosed herein or elsewhere.

In some embodiments, the subject has been medically diagnosed as havingAD by exhibiting clinical (e.g., physical) symptoms of the disease. Insome patients the appearance of sleep-related disorder precede aclinical diagnosis of AD. Therefore, in some embodiments, the compoundsor compositions disclosed herein are administered prior to a clinicaldiagnosis of AD.

e. Traumatic Brain Injury

In another particular embodiment, the disclosed compositions are used totreat a subject suffering from traumatic brain injury (TBI). Traumaticbrain injury occurs when an external mechanical force, typically headtrauma, causes brain dysfunction.

Traumatic brain injury can have wide-ranging physical and psychologicaleffects. Some signs or symptoms may appear immediately after thetraumatic event, while others may not appear until days or weeks later.Symptoms of TBI include, but are not limited to, loss of consciousness;a state of being dazed, confused or disoriented; memory or concentrationproblems; headache, dizziness or loss of balance; nausea or vomiting;sensory problems such as blurred vision, ringing in the ears or a badtaste in the mouth; sensitivity to light or sound; mood changes or moodswings; feeling depressed or anxious; fatigue or drowsiness; difficultysleeping; sleeping more than usual, agitation, combativeness or otherunusual behavior; slurred speech; inability to awaken from sleep;weakness or numbness in fingers and toes; loss of coordination;convulsions or seizures, dilation of one or both pupils of the eyes;and/or clear fluids draining from the nose or ears. In children,additional symptoms include change in eating or nursing habits;persistent crying and inability to be consoled; unusual or easyirritability; change in ability to pay attention; change in sleephabits; sad or depressed mood; and/or loss of interest in favorite toysor activities.

TBI can be diagnosed using the Glasgow Coma Scale, a 15-point test thathelps a doctor or other emergency medical personnel assess the initialseverity of a brain injury by checking a person's ability to followdirections and move their eyes and limbs. The coherence of speech alsoprovides important clues. Abilities are scored numerically with higherscores indicating more mild injury. Imaging such as computerizedtomography (CT) and magnetic resonance imaging (MRI), as well asintracranial pressure monitoring can also be used to assist in thediagnoses by helping to identify the local(s) and extent of the trauma.

Conventional treatments for TBI include administration of agents such asdiuretics, anti-seizure drugs, and coma-inducing drugs; surgery toremove clotted blood, repair skull fractures, and/or relieve pressureinside the skull.

IV. Methods of Increasing Tonic Inhibition

Method of using 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), aderivative thereof, or a pharmaceutically acceptable salt thereof forincreasing tonic inhibition are also provided. The methods can be usedto increase tonic inhibition in a subject with a disease or disordercharacterized by a defect or deficiency in tonic inhibition. Exemplarydiseases include neurogenetic diseases such as Fragile X syndrome orAngelman syndrome.

A. Treatment Protocol

1. Tonic Inhibition

The disclosed methods for increasing tonic inhibition in a subjecttypically include administering to a subject in need thereof aneffective amount of THIP or a derivative thereof to increase tonicinhibition in the brain of the subject.

Neural inhibition in the mammalian brain is mediated by two fasttransmitters, glycine and gamma-aminobutyric acid (GABA) (Jonas andBuzaki, Scholarpedia, 2(9):3286 (2007)). Glycine is the major inhibitorytransmitter in the spinal cord, while GABA is the major transmitter inhigher brain regions. GABA released from presynaptic terminals canactivate three different types of receptors: GABA receptors (GABARs)type A, B, and C. Neural inhibition can be “phasic” or “tonic”. Phasicinhibition is a short-lasting inhibition most often generated by theactivation of GABAA receptors following action potentials in apresynaptic interneuron. Among several long-lasting forms of inhibitionis tonic GABAA conductance activated by ambient GABA in theextracellular space. Tonic inhibition is mediated by molecularly andfunctionally specialized GABAA receptors containing alpha6 or deltasubunits, and which display a high affinity for GABA binding. THIP, is asuperagonist of the δ-subunit-containing presynaptic and extrasynapticGABA A receptors that mediates strong tonic inhibitory conductance inthe CNS (Brown, et al., Br. J. Pharmacol., 136:965-974 (2002), Glykys,et al., J Physiol., 582:1163-1178 (2007), Brown, et al., Cell,107:477-487 (2001).

Therefore, THIP can be used to increase tonic inhibition is a subject inneed thereof.

In vitro and animal model studies show that reduced tonic inhibition canbe an underlying cause of some neurogenetic diseases. For example,studies show that decreased concentrations of GABA can lead to decreasedtonic inhibition of cerebellar granule cells which is the underlyingcause of cerebellar ataxia in Angelman syndrome (Egawa, et al., ScienceTranslational Medicine, 4:163ra157 (2012)). Treatment with THIP (500 nM)increased tonic holding currents and reduced the excitability ofcerecellar ganule cells from a mouse model of Angelman syndrome rescuingthe defect. Doses of THIP (1.25 mg/kg and 2.5 mg/kg) were effective torescue cerebellar dysfunction in vivo (reduced hind paw abductionwithout effective width or stride), while low effective doses (e.g.,1.25 mg/kg) were effective to rescue cerebellar dysfunction withoutadverse effects (reduced time on rotarod).

Studies also show that impaired GABAergic transmission in differentbrain regions such as the amygdala, striatum, or cerebral cortexcontributes to neuron excitability deficits and behavioral abnormalitiesin Fragile X syndrome (Olmos-Serrano, et al., Dev. Neurosci., 33:395-403(2011), Olmos-Serrano, et al., J. Neurosci., 30(29):9929-9938 (2010),Braat and Kooy, Drug Discovery Today, 19(4):510-519 (2014)). In vitroexperiments reveled that augmentation of tonic inhibitory tone usingTHIP rescued the decreased bioavailability of GABA and reduced toniccurrents of principal neurons of the BL amygdala of Fmr1 knockout mice.Furthermore, THIP treatment improved a number of Fragile X phenotypes inFmr1 knockout mice in vivo, including, reduction or dampening ofhyperactivity (e.g., measured by travel and velocity), and reduction ofhypersensitivity to auditory stimuli.

2. Dosage and Administration

The disclosed methods of increasing tonic inhibition typically includeadministering a subject in need thereof an effective amount of THIP or aderivative thereof, preferably is a pharmaceutically acceptablecomposition such as those discussed in more detail above.

The effective amount or therapeutically effective amount is typically adosage sufficient to increase tonic inhibition of neurons in the brainof the subject. In some embodiment the method reduces or prevents one ormore neuropsychiatric morbidities or phenotypes in a subject with aneurogenetic disease or disorder as discussed in more detail below.Therefore, the amount can be effective to treat or prevent one or moresymptoms of a neurogenetic disease, or to otherwise provide a desiredpharmacologic and/or physiologic effect, for example.

The precise dosage will vary according to a variety of factors such assubject-dependent variables (e.g., age, immune system health, clinicalsymptoms etc.). Exemplary dosages, symptoms, pharmacologic, andphysiologic effects are discussed in more detail below.

Particularly preferred embodiments include formulations for extendedrelease. For example, the formulation can suitable for administrationonce daily or less. In some embodiments, the composition is onlyadministered to the subject once every 24-48 hours.

The timing of the administration of the composition will depend on theformulation and/or route of administration used. In some embodiments,administration of the composition will be given as a long-term treatmentregimen whereby pharmacokinetic steady state conditions will be reached.

A preferred route of administration is transdermal, for example, atransdermal patch that is contacted with the skin of the subject.

In general, by way of example only, dosage forms useful in the disclosedmethods can include doses in the range of 0.1 to 1,000 mg, 1 to 200 mg,5 to 175 mg, 7.5 to 150 mg, or 10 to 125 mg, or 12.5 to 150 mg, or 15 to125 mg, or 17.5 to 100 mg, or 20 to 75 mg, or 22.5 to 60 mg, or 25 to 50mg, with doses of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg,40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 75 mg, and 100 mg being specificexamples of preferred doses. Typically, such dosages are administeredonce, twice, or three times daily, or every other day to a human.

A typical oral dose form preferably includes from about 2.5 mg to about30 mg THIP. Preferably, the THIP is in a crystalline form. Furtherembodiments of the medicament comprises an effective amount of THIP from2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18mg, or 18 mg to 20 mg, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg,17.5 mg, or 20 mg. A typical embodiment is about 5 mg to about 20 mg ofcrystalline THIP, such as the hydrochloride of THIP. Typically, suchdosages are administered once, twice, or three times daily, or everyother day to a human. In some embodiments, the total amount administeredto a subject in 24 hour period is 1 mg to 50 mg. In some embodiments,the subject is started at a low dose and the dosage is escalated in thedrug is well tolerated in the subject.

In the most preferred embodiments, the dosage is effective to increasetonic inhibition without causing an adverse effect in the subject.Adverse effects can include, for example, induced neuronal dysfunctionand negative effects on the function of thalamo-cortical network, suchas increased frequency of seizures or excessive drowsiness or daytimesomnolence. The animals models discussed above utilize a dosage of 1.25mg/kg to 3 mg/kg in mice. In a particular animal model, a dosage of 1.25mg/kg was preferred over a dosage of 2.5 mg/kg because there were feweradverse effects. Therefore in some embodiments, the dosage is about 0.1mg/kg to about 5 mg/kg, preferably wherein there are few or no adverseeffects. Dosages can be scaled from mouse to human using conversionsthat are known in the art. Because this therapy typically includesadministration during a time when the subject is active, the dosage alsopreferably does not induce a sedative effect in the subject.

In some embodiments, the effect of the composition on a subject iscompared to a control. For example, the effect of the composition on aparticular symptom, pharmacologic, or physiologic indicator can becompared to an untreated subject, or the condition of the subject priorto treatment. In some embodiments, the symptom, pharmacologic, orphysiologic indicator is measured in a subject prior to treatment, andagain one or more times after treatment is initiated. In someembodiments, the control is a reference level, or average determinedbased on measuring the symptom, pharmacologic, or physiologic indicatorin one or more subjects that do not have the disease or condition to betreated (e.g., healthy subjects). In some embodiments, the effect of thetreatment is compared to a conventional treatment that is known the art,such as one of those discussed herein.

B. Conditions, Symptoms, Subjects, and Diseases to be Treated

In some embodiments, subjects in need of tonic inhibition are subjectswith a neurogenetic disease. In some embodiments, the composition isadministered in an effective amount to reduce or prevent one or moresymptoms or phenotypes of the disease. Diseases and symptoms thereof arediscussed in more detail below.

1. Angelman Syndrome

In some embodiments, the composition is used to treat a subject withAngelman syndrome. Angelman syndrome is a neurogenetic disorder causedby deletion or inactivation of genes on the maternally inheritedchromosome 15 while the paternal copy, which may be of normal sequence,is imprinted and silenced. Prader-Willi syndrome, is caused by a similarloss of paternally inherited genes and maternal imprinting.

Symptoms of Angelman syndrome include: consistent symptoms which areexhibited in 100% of cases, frequent symptoms which occur in more than80% of cases, and associated which occur in 20-80% of cases. Consistentsymptoms include developmental delay; speech impairment, no or minimaluse of words; receptive and non-verbal communication skills higher thanverbal ones; movement or balance disorder; usually ataxia of gait and/ortremulous movement of limbs; and behavioral uniqueness such as frequentlaughter/smiling, apparent happy demeanor, easily excitable personality,often with hand flapping movements, hypermotoric behavior, shortattention span, or any combination thereof. Frequent symptoms includedelayed, disproportionate growth in head circumference, usuallyresulting in microcephaly (absolute or relative) by age 2; seizures,onset usually <3 years of age; and abnormal EEG having a characteristicpattern with large amplitude slow-spike waves. Associated symptomsinclude strabismus; hypopigmented skin and eyes; tongue thrusting;suck/swallowing disorders; hyperactive tendon reflexes; feeding problemsduring infancy; uplifted, flexed arms during walking; prominentmandible; increased sensitivity to heat; wide mouth, wide-spaced teeth;sleep disturbance; frequent drooling, protruding tongue; attractionto/fascination with water; excessive chewing/mouthing behaviors; flatback of head; smooth palms; attraction to/fascination with water;fascination with crinkly items such as certain papers and plastics;abnormal food related behaviors; obesity (in the older child);scoliosis; and constipation.

Other common symptoms of Angelman syndrome as well as methods ofdiagnoses are discussed in Williams, et al., American Journal of MedicalGenetics, 140A:413-418 (2006), which is specifically incorporated byreferenced herein in its entirety.

2. Fragile X Syndrome

In some embodiments, the composition is used to treat a subject withFragile X syndrome (FXS). Fragile X syndrome is a neurogenetic disorder.It is the most common single-gene cause of autism and an inherited causeof intellectual disability especially among boys. FXS is related to theexpansion of the CGG trinucleotide repeat affecting the Fragile X mentalretardation 1 (FMR1) gene on the X chromosome. In normal individuals,this DNA segment is repeated from 5 to about 40 times. In people withfragile X syndrome, the CGG segment is repeated more than 200 times,which leads to silencing of the gene. Loss or a shortage (deficiency) ofFMR1 disrupts nervous system functions and leads to the signs andsymptoms of fragile X syndrome.

In addition to intellectual disability, prominent characteristics andsymptoms of the syndrome can include an elongated face, large orprotruding ears, flat feet, larger testes (macroorchidism), and lowmuscle tone; recurrent otitis media (middle ear infection) and sinusitisis common during early childhood; speech may be cluttered or nervous;stereotypic movements (e.g., hand-flapping) and atypical socialdevelopment, particularly shyness, limited eye contact, memory problems,and difficulty with face encoding; psychiatric problems includingattention deficit hyperactive disorder, obsessive-compulsive disorder,mood disorders, dementia, and anxiety disorders; hypersensitivity andrepetitive behavior including very short attention spans, hyperactivity,and hypersensitivity to visual, auditory, tactile, and olfactorystimuli, and perseveration; ophthalmologic problems such as strabismusand amblyopia; neurological complications such as seizures; problems inperforming tasks that require the central executive of working memory;and premature menopause. Some individuals with fragile X syndrome alsomeet the diagnostic criteria for autism.

Diagnosis of fragile X syndrome is made through genetic testing todetermine the number of CGG repeats. Although at least 200 repeats areneeded for a diagnosis of FXS, males and females with 55 to 200 repeatsof the CGG segment are said to have an FMR1 gene premutation. Mostpeople with a premutation are intellectually normal, however, someindividuals with a premutation have lower than normal amounts of FMRP.As a result, they may have mild versions of the physical symptoms of thedisease and may experience emotional problems such as anxiety ordepression.

In some embodiments, the subject has Fragile X-associated tremor/ataxiasyndrome (FXTAS).

3. Rett Syndrome

In some embodiments, the composition is used to treat a subject withRett Syndrome, also referred to as cerebroatrophic hyperammonemia. Rettsyndrome is a neurodevelopmenal disorder that most often affectsfemales. Genetically, Rett syndrome is most typically caused by amutation in the gene MECP2 located on the X chromosome. The mutation canarise sporadically or from germline mutations, but is not typicallyinherited. In less than 10% of Rett syndrome cases, mutations in thegenes CDKL5 or FOXG1 have also been found. Rett syndrome is initiallydiagnosed by clinical observation, but the diagnosis is definitive whenthere is a genetic defect in the MECP2 gene.

The onset and severity of Rett syndrome vary from subject to subject.Before the onset of symptoms, the child generally appears to grow anddevelop normally. Early subtle abnormalities even in early infancy, caninclude loss of muscle tone (hypotonia), difficulty feeding, andjerkiness in limb movements. Next, gradually, mental and physicalsymptoms begin to manifest. The subject loses purposeful use of herhands and the ability to speak, and can experience other early symptomsincluding problems crawling or walking and diminished eye contact. Theloss of functional use of the hands is followed by compulsive handmovements such as wringing and washing. Apraxia, the inability toperform motor functions, can interfere with all body movements,including eye gaze and speech.

Children with Rett syndrome can also exhibit autistic-like behaviorssuch as incontinence, screaming fits, inconsolable crying, breathholding, hyperventilation & air swallowing, avoidance of eye contact,lack of social/emotional reciprocity, markedly impaired use of nonverbalbehaviors to regulate social interaction, loss of speech, and sensoryproblems. Other symptoms include walking on the toes, sleep problems, awide-based gait, teeth grinding and difficulty chewing, slowed growth,seizures, cognitive disabilities, and apnea (breath holding), possibleshort stature, sometimes with unusual body proportions because ofdifficulty walking or malnutrition caused by difficulty swallowing,hypotonia, delayed or absent ability to walk, ataxia, microcephaly,gastrointestinal problems, some forms of spasticity, chorea, anddystonia.

There is currently no cure for Rett syndrome, but restoration of MECP2,for example using Insulin-like Growth Factor-1 (IGF-1) has shown promisein a mouse model (Tropea, et al., Proc Natl Acad Sci USA., 106(6):2029-2034 (2009)). NMDA receptor antagonists have also shown promise.Symptoms can also be treated using, for example, sleep aids, selectiveserotonin reuptake inhibitors (SSRIs), anti-psychotics (for self-harmingbehaviors), beta-blockers (for long QT syndrome), and agents to managegastrointestinal dysfunction and malnutrition.

4. Autism Spectrum Disorders

In some embodiments, the composition is used to treat a subject withAsperger's syndrome, pervasive developmental disorder, not otherwisespecified (PDD-NOS), autistic disorder, or another autism spectrumdisorder.

Autism spectrum disorder (ASD) is a range of neurodevelopment disorders,generally characterized by social impairments, communicationdifficulties, and restricted, repetitive, and stereotyped patterns ofbehavior. Autistic disorder, also referred to as autism or classicalASD, is the most severe form of ASD. Children with classic ASD exhibitimpairments involving social and language function as well as repetitivebehaviors that are typically more severe than in children with otherspectrum disorders. Often, they also have mental retardation and/orseizures.

Other conditions along the autism spectrum include Asperger syndrome,and PDD-NOS. Asperger's syndrome (AS) is the mildest form of autism.Children with AS become obsessively interested in a single object orsubject. They often learn all about their preferred subject and discussit continuously. Social skills are typically markedly impaired in ASchildren, and they are often awkward and uncoordinated.

Symptoms of PDD-NOS can vary widely from one child to the next. Overall,child with PDD-NOS can be characterized as having impaired socialinteraction, better language skills than kids with autistic disorder butnot as good as those with Asperger's syndrome, fewer repetitivebehaviors than children with Asperger's syndrome or autistic disorder,and a later age of onset. There are no agreed-upon criteria fordiagnosing a subject with PDD-NOS. A child can be diagnosed with PDD-NOSif the child seems autistic to professional evaluators but does not meetall the criteria for autistic disorder.

Pharmaceutical interventions typically limited to treatment of specificautism-related symptoms, such as anxiety, depression, orobsessive-compulsive disorder. Antipsychotic medications can be used totreat behavioral problems. Seizures can be treated with one or moreanticonvulsant drugs. Medication used to treat attention deficitdisorder can be used reduce impulsivity and hyperactivity in autismspectrum subjects.

V. Combination Therapies

In some embodiments, THIP or a derivative thereof is administered incombination with one or more additional active agents. The combinationtherapies can include administration of the active agents together inthe same admixture, or in separate admixtures. Therefore, in someembodiments, the pharmaceutical composition includes two, three, or moreactive agents. Such formulations typically include an effective amountof THIP or a derivative. The different active agents can have the same,or different mechanisms of action. In some embodiments, the combinationresults in an additive effect on the treatment of the disease ordisorder. In some embodiments, the combinations results in a more thanadditive effect on the treatment of the disease or disorder.

The pharmaceutical compositions can be formulated as a pharmaceuticaldosage unit, also referred to as a unit dosage form.

A THIP or a derivative can be the singular active agent administered toincrease slow wave sleep, to increase tonic inhibition, to treat aneurogenetic disorder, a neurodegenerative disease, a central nervoussystem disorder, or a symptom or pathology thereof; or THIP or aderivative thereof can be administered in combination with another agentincrease slow wave sleep, to reduce or prevent cognitive impairment, totreat a neurodegenerative disease, a central nervous system disorder, ora symptom or pathology thereof.

In particular embodiments, a combination therapy includes THIP or aderivative thereof and one or more conventional treatments forneurodegeneration, or for increasing or enhancing neuroprotection, suchas those discussed herein. Exemplary neuroprotective agents are known inthe art and include, for example, glutamate antagonists, antioxidants,and NMDA receptor stimulants. Other neuroprotective agents andtreatments include caspase inhibitors, trophic factors, anti-proteinaggregation agents, therapeutic hypothermia, and erythropoietin. In someembodiments, THIP or derivative thereof is administered to a subject incombination with a treatment that increase nerve regeneration.

In a particular embodiment, THIP or a derivative thereof is administeredto a subject in combination with a conventional treatment forHuntington's disease, such as a dopamine blocker to help reduce abnormalbehaviors and movements, or a drug such as amantadine and tetrabenazineto control movement, etc. Other drugs that help to reduce chorea includeneuroleptics and benzodiazepines. Compounds such as amantadine orremacemide have shown preliminary positive results. Hypokinesia andrigidity, especially in juvenile cases, can be treated withantiparkinsonian drugs, and myoclonic hyperkinesia can be treated withvalproic acid. Psychiatric symptoms can be treated with medicationssimilar to those used in the general population. Selective serotoninreuptake inhibitors and mirtazapine have been recommended fordepression, while atypical antipsychotic drugs are recommended forpsychosis and behavioral problems.

In another particular embodiment, THIP or a derivative thereof isadministered to a subject in combination with a conventional treatmentfor Parkinson's disease, such as levodopa (usually combined with a dopadecarboxylase inhibitor or COMT inhibitor), a dopamine agonist, or anMAO-B inhibitor. Other common agents that can be used in combination thedisclosed combinations include amantadine and anticholinergics fortreating motor symptoms, clozapine for treating psychosis,cholinesterase inhibitors for treating dementia, and modafinil fortreating daytime sleepiness.

In another particular embodiment, THIP or a derivative thereof isadministered to a subject in combination with a conventional treatmentfor ALS such as the antiexcitotoxin riluzole (RILUTEK®)(2-amino-6-(trifluoromethoxy) benzothiazole). Other medications, mostused off-label, and interventions can reduce symptoms due to ALS. Sometreatments improve quality of life and a few appear to extend life.Common ALS-related therapies are reviewed in Gordon, Aging and Disease,4(5):295-310 (2013), which is specifically incorporated by referenceherein in its entirety. Exemplary ALS treatments and interventions areprovided in Table 1, below, which is adapted from Gordon, Aging andDisease, 4(5):295-310 (2013).

TABLE 1 Treatments for ALS Treatment Administration Indication *Riluzole50 mg bid ALS *Multidisciplinary care Every three monthly All symptomsvisits of ALS *Non-invasive ventilation Nighttime and during Respiratorysymptoms at least 4 insufficiency hours/day Gastrostomy Daily calorieDysphagia and supplements malnutrition *Dextromethorphan/quinidine 20mg/10 mg bid Pseudobulbar affect Diaphragm Pacing Up to 24 hours/dayRespiratory insufficiency Brain-computer interface ExperimentalCommunication Amitriptyline 12.5-125 mg qhs Anxiety SSRI antidepressants20-100 mg qd Mirtazapine 15-30 mg qhs Buspirone 10 mg tid Diazepam 2-10mg tid Lorazepam 0.5-2 mg tid Mirtazapine 15-30 mg qhs SSRIantidepressants 10-100 mg qd Diazepam 2-10 mg tid Cramps Phenytoin100-300 mg qhs Vitamin E 400 IU tid Mirtazapine 15-30 mg qhs DepressionSSRI antidepressants 20-100 mg qd Tricyclic antidepressants 12.5-150 mgqhs Venlafaxine 37.5-75 mg qd Amantadine 100 mg qAM, qnoon FatigueBupropion SR 150-450 mg qd Fluoxetine 20-80 mg qd Pemoline 18.75-93.75mg qd Pyridostigmine 60 mg tid Venlafaxine 75-225 mg qd Amitriptyline12.5-125 mg qhs Atropine sulphate 0.4 mg q4-6 h Sialorrhea 1-2ophthalmic drops SL q4-6 h Diphenhydramine 25-50 mg tid Hyoscyaminesulfate 0.125-0.25 mg q4 h Scopolamine transdermal 0.5 mg q72 h patchBaclofen 10-60 mg tid Spasticity Benzodiazepines 2-10 mg tid Dantrolene25-100 mg tid Tizanidine 2-8 mg tid Amitriptyline 12.5-75 mg qhs UrinaryOxybutynin 2.5-5 mg bid urgency 3.9 mg patch qd Tolterodine 1-2 mg bidBid = twice daily; IU = international units; qAM = every morning; qd =daily; qhs = every day; qt = bedtime; qid = four times daily; qnoon =every day at noon; q × h = every × hours; SL = sublingual; SR = slowrelease; SSRI = serotonin-specific reuptake inhibitor; tid = three timesdaily. *shown to have a beneficial effect in ALS

A number of other agents have been tested in one or more clinical trialswith efficacies ranging from non-efficacious to promising. Exemplaryagents are reviewed in Carlesi, et al., Archives Italiennes de Biologie,149:151-167 (2011). For example, in some embodiments, THIP or aderivative thereof, is administered to a subject in combination with anagent that reduces excitotoxicity such as talampanel(8-methyl-7H-1,3-dioxolo(2,3)benzodiazepine), a cephalosporin such asceftriaxone, or memantine; an agent that reduces oxidative stress suchas coenzyme Q10, manganoporphyrins, KNS-760704[(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diaminedihydrochloride, RPPX], or edaravone(3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186); an agent that reducesapoptosis such as histone deacetylase (HDAC) inhibitors includingvalproic acid, TCH346(Dibenzo(b,f)oxepin-10-ylmethyl-methylprop-2-ynylamine), minocycline, ortauroursodeoxycholic Acid (TUDCA); an agent that reducesneuroinflammation such as thalidomide and celastol; a neurotropic agentsuch as insulin-like growth factor 1 (IGF-1) or vascular endothelialgrowth factor (VEGF); a heat shock protein inducer such as arimoclomol;or an autophagy inducer such as rapamycin or lithium.

In another particular embodiment, THIP or a derivative thereof isadministered to a subject in combination with a conventional treatmentfor AD, for example, acetylcholinesterase inhibitor such as tacrine,rivastigmine, galantamine or donepezil; or an NMDA receptor antagonistsuch as memantine, or an antipsychotic drug.

In some embodiments, the active agent(s) is administered in combinationwith a co-therapy such as dietary changes with or without dietarysupplements, exercise, psychological and/or psychosocial counseling,physical therapy, occupational therapy, and speech therapy.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

EXAMPLES

The Examples provided herein are included solely for augmenting thedisclosure herein and should not be considered to be limiting in anyrespect.

Example 1 Evaluation of Gaboxadol in Resident Intruder Test in Mice

Behavioral aggression is a common symptom associated with Alzheimer'sdisease. The Resident-Intruder (RI) test is a behavioral test that canassess aggression in male mice. The two output measures are latency toattack and total number of attacks during the test. 40 Male APP/PS1 HETand 10 Male APP/PS1 WT were used as “residents”. Male C57BL/6J mice wereused as intruders. Average body weight (grams) prescreen is shown inFIG. 1.

Certain variables outside of genotype differed between experiments:

-   -   animal age (>2 vs. >6 months for Fmr1 and APP/PS1)    -   housing conditions (APP/PS1 were single housed for 3 weeks ahead        of testing)    -   lab, diet, and potentially lighting        Many other key variables were the same:    -   route and timing of drug admin (i.p injection 30 min ahead of        testing)    -   gender (male only)    -   genetic background (C57BL/6J)    -   10 animals/group

1. Resident-Intruder Prescreen:

Mice were screened for baseline aggression in the Resident Intrudertest. Mice with attack latencies exceeding 150 seconds were excludedfrom the study. Mice were then balanced by latency to first attack,attack frequency, and body weight. Attack latency (seconds) prescreen isshown in FIG. 2. Attack frequency (count) prescreen is shown in FIG. 3.

2. Resident-Intruder Test 1:

Gaboxadol (referred to as Test compound A) was tested at 0.5, 1, and 2mg/kg following IP injection, 30 min pre-treat time. Mice were tested inResident-Intruder paradigm for 5 minutes test duration. Average bodyweight is shown in FIG. 4.

3. Findings: [Attack Latency Test 1]

APP/PS1 HET mice treated with vehicle exhibited a significantly shorterlatency to first attack compared to APP/PS1 WT-Vehicle mice.

Test Compound A (gaboxadol) (0.5, 1, and 2 mg/kg) significantlyincreased the latency to first attack in HET mice compared to vehicle.Results (latency to attack) in seconds are shown in FIG. 5.

4. Findings [Attack Frequency Test 1]

APP/PS1 HET mice treated with Vehicle exhibited a significantly greaterattack frequency compared to APP/PS1 WT-Vehicle mice.

As shown in FIG. 6, treatment with Test Compound A (gaboxadol) (0.5. 1,and 2 mg/kg) significantly attenuated the increase in attack frequencyin HET mice.

Administration of gaboxadol normalizes heightened aggression in thisAlzheimer disease model.

Example 2 Effect of Gaboxadol on Locomotor Activity in Mice

10 male C57 mice were administered 0.9% NaCl, and gaboxadol: 1.25 mg/Kg,2.5 mg/Kg and 5 mg/Kg by i.p injection 30 min ahead of testing. Results,in terms of total distance traveled in inches v. time in minutes, areshown in FIG. 7.

10 male Balb/Cbyj mice were administered 0.9% NaCl, and gaboxadol: 1.25mg/Kg, 2.5 mg/Kg and 5 mg/Kg by i.p injection 30 min ahead of testing.Results, in terms of total distance traveled in inches v. time inminutes, are shown in FIG. 8.

As shown in FIGS. 7 and 8, administration of gaboxadol was not sedating.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A method of treating Dementia with Lewy Bodiescomprising administering to a patient in need thereof gaboxadol or apharmaceutically acceptable salt thereof.
 2. A method of treatingDementia with Lewy Bodies comprising administering to a patient in needthereof gaboxadol or a pharmaceutically acceptable salt thereof and acompound selected from the group consisting of memantine, galantamine,donepezil and rivastigmine.
 3. The method of claim 2, wherein memantineor a pharmaceutically acceptable salt thereof is administered at adosage of between about 1 mg to about 30 mg.
 4. The method of claim 2,wherein memantine or a pharmaceutically acceptable salt thereof isadministered at a dosage of about 5 mg or 10 mg.
 5. The method of claim2, wherein memantine or a pharmaceutically acceptable salt thereof isadministered at a dosage of about 7 mg, 14 mg, 21 mg, or 28 mg in aconventional release dosage form or an extended release dosage form. 6.The method of claim 1, wherein the patient is administered 0.1 mg to 50mg gaboxadol or a pharmaceutically acceptable salt thereof.
 7. Themethod of claim 1, wherein the patient is administered 2.5 mg to 30 mggaboxadol or a pharmaceutically acceptable salt thereof.
 8. The methodof claim 1, wherein the patient is administered a dose of gaboxadol or apharmaceutically acceptable salt thereof ranging from 0.1 mg/kg to 3.0mg/kg.
 9. The method of claim 2, wherein the patient is administered 1.0mg to 30 mg galantamine or a pharmaceutically acceptable salt thereof.10. The method of claim 2, wherein the patient is administered extendedrelease galantamine or a pharmaceutically acceptable salt thereof at adosage of 8 mg, 16 mg, or 24 mg.
 11. The method of claim 2, wherein thepatient is administered 1.0 mg to 30 mg donepezil or a pharmaceuticallyacceptable salt thereof.
 12. The method of claim 2, wherein the patientis administered donepezil or a pharmaceutically acceptable salt thereofat a dosage of 5 mg, 10 mg, or 23 mg.
 13. The method of claim 2, whereinthe patient is administered 1.0 mg to 20 mg rivastigmine or apharmaceutically acceptable salt thereof.
 14. The method of claim 2,wherein the patient is administered rivastigmine or a pharmaceuticallyacceptable salt thereof at a dosage of 4.6 mg, 9.5 mg, or 13.3 mg. 15.The method of claim 2, wherein the patient is administered an oralsolution of rivastigmine or a pharmaceutically acceptable salt thereofat a dosage of 1 mg/ml.
 16. The method of claim 1, wherein the patientis administered a subtherapeutic dosage of memantine or apharmaceutically acceptable salt thereof, galantamine or apharmaceutically acceptable salt thereof, donepezil or apharmaceutically acceptable salt thereof, or rivastigmine or apharmaceutically acceptable salt thereof.
 17. The method of claim 1,wherein the patient is administered about 1 mg to about 20 mg gaboxadolor a pharmaceutically acceptable salt thereof.
 18. The method of claim1, wherein the patient is administered about 1 mg to about 15 mggaboxadol or a pharmaceutically acceptable salt thereof.
 19. The methodof claim 1, wherein the patient is administered about 1 mg to about 10mg gaboxadol or a pharmaceutically acceptable salt thereof.
 20. Themethod of claim 1, wherein the patient is administered about 5 mg orabout 10 mg gaboxadol or a pharmaceutically acceptable salt thereof. 21.The method of claim 1, further comprising administering memantine or apharmaceutically acceptable salt thereof.